Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors

ABSTRACT

The invention relates to novel pyrrolopyridinone derivatives of the formula (I) or (II):  
                 
 
     pharmaceutical compositions containing the compounds and their use for the treatment of sexual dysfunction.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. provisionalapplication Ser. No. 60/204,646 filed May 17, 2000, the contents ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to novel pyrrolopyridinone derivatives,intermediates used in, synthesis of and pharmaceutical compositionscontaining the compounds and their use for the treatment of sexualdysfunction. The compounds of the present invention arephosphodiesterase inhibitors useful for the treatment of sexualdysfunction, more particularly male erectile dysfunction.

BACKGROUND OF THE INVENTION

[0003] Erectile dysfunction (ED) is defined as the inability to achieveor maintain an erection sufficiently rigid for satisfactory sexualintercourse. Currently it is estimated that approximately 7-8% of themale population suffer from some degree of ED, the equivalent of atleast 20 million men in the United States alone. Since the likelihood ofED increases with age, it is projected that the incidence of thiscondition will rise in the future as the average age of the populationincreases.

[0004] Male erectile dysfunction may be the consequence of psychogenicand/or organic factors. Although ED is multi-factorial, certainsub-groups within the male population are more likely to present withthe symptoms of the disorder. In particular, patients with diabetes,hypertension, heart disease, and multiple sclerosis have a particularlyhigh prevalence of ED. In addition, patients who take certain classes ofdrugs such as antihypertensives, antidepressants, sedatives, andanxiolytics are more prone to suffer from ED.

[0005] Treatments for ED include a variety of pharmacologic agents,vacuum devices, and penile prostheses. Among the pharmacologic agents,papaverine, phentolamine, and alprostadil are currently used inpractice. These agents are only effective after direct intracavernosalor intraurethral injection, and are associated with side effects such aspriapism, fibrosis, penile pain and hematoma at the injection site.Vacuum devices are a noninasive alternative treatment for ED. Thesedevices produce an erection by creating a negative pressure around theshaft of the penis resulting in an increased blood flow into the corpuscavernosum via passive arterial dilation. Although this form of therapyis frequently successful in ED of organic origin, complaints include thelack of spontaneity and the time involved in using a mechanical device,and difficulty and discomfort with ejaculation. A variety of semi-rigidor inflatable penile prostheses have been used with some success,particularly in diabetic men. These devices are generally consideredwhen other treatment options have failed, and are associated with anincreased risk of infection and ischemia.

[0006] Recently, the phosphodiesterase V (PDEV) inhibitor, sildenafil(Viagra®) was approved by the FDA as an orally effective medication forthe treatment of ED. Sildenafil,5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-oneand a number of related analogs and their use as antianginal agents aredescribed in U.S. Pat. Nos. 5,250,534 and 5,346,901. The use ofsildenafil and related analogs for treating male erectile dysfunction isdescribed in PCT International Application Publication No. WO 94/28902,published Dec. 22, 1994. In clinical studies, the drug improved sexualfunction in about 70% of the men who suffer from ED of psychogenic ororganic etiology. However, the drug showed less dramatic efficacy inpatients who had undergone a radical prostatectomy, with improvederections in 43% of patients who took sildenafil versus 15% on placebo.In addition, the use of sildenafil is associated with severalundesirable side effects including headache, flushing and disruptedcolor vision which result from non-selective effects on a variety oftissues. In spite of these shortcomings, the drug is viewed by patientsas preferable to other treatments which involve the introduction ofmedication directly into the penis via injection, the use of an externaldevice or a surgical procedure.

[0007] Daugan et.al, in U.S. Pat. No. 5,859,009 and EP 0740668 B1describe the synthesis of a series of tetracyclic derivatives asinhibitors of cyclic guanosine 3′, 5′ monophosphate specificallyphosphodiesterase, and their use in treating cardiovascular disorders.Daugan et.al., in WO97/03675 teach the use of the tetracyclicderivatives for the treatment of impotence.

[0008] Garinaux, J.-F. et al., in Tetrahedron Letters 38(17), (1997), pp2997-3000 disclose the synthesis of tricyclic quinolone derivatives viaoxidation of 1,2,3,4-tetrahydro-β-carbolines.

[0009] Pfenninger, E. in DE 2803541 and U.S. Pat. No. 4,235,907discloses substituted 9H-pyrrolo-[3,4-b]quinolin-9-ones and their use inthe treatment of allergic asthma.

[0010] Sexually stimulated penile erection results from a complexinterplay of physiological processes involving the central nervoussystem, the peripheral nervous system, and the smooth muscle.Specifically, release of nitric oxide from the non-adrenergic,non-cholinergic nerves and endothelium activates guanylyl cyclase andincreases intracellular cGMP levels within the corpus cavernosum. Theincrease in intracellular cGMP reduces intracellular calcium levels,resulting in trabecular smooth muscle relaxation, which, in turn,results in corporal volume expansion and compression of the sub-tunicalvenules leading to penile erection.

[0011] PDEV has been found in human platelets and vascular smoothmuscle, suggesting a role for this enzyme in the regulation ofintracellular concentrations of cGMP in cardiovascular tissue. In fact,inhibitors of PDEV have been shown to produce endothelial-dependentvasorelaxation by potentiating the increases in intracellular cGMPinduced by nitric oxide. Moreover, PDEV inhibitors selectively lower thepulmonary arterial pressure in animal models of congestive heart failureand pulmonary hypertension. Hence in addition to their utility in ED,PDEV inhibitors would likely be of therapeutic benefit in conditionslike heart failure, pulmonary hypertension, and angina.

[0012] Agents that increase the concentration of cGMP in penile tissue,either through enhanced release or reduced breakdown of cGMP, areexpected to be effective treatments for ED. The intracellular levels ofcGMP are regulated by the enzymes involved in its formation anddegradation, namely the guanylate cyclases and the cyclic nucleotidephosphodiesterases (PDEs). To date, at least nine families of mammalianPDEs have been described, five of which are capable of hydrolyzing theactive, cGMP, to the inactive, GMP, under physiological conditions (PDEsI, II, V, VI, and IX). PDE V is the predominant isoform in human corpuscavernosum. Inhibitors of PDEV, therefore, would be expected to increasethe concentration of cGMP in the corpus cavernosum and enhance theduration and frequency of penile erection.

[0013] Additionally, selective PDE inhibitors are known to be useful inthe treatment of various disorders and conditions including maleerectile dysfunction (ED), female sexual arousal dysfunction, femalesexual dysfunction related to blood flow and nitric oxide production inthe tissues of the vagina and clitoris, premature labor, dysmenorrhea,cardiovascular disorders, atherosclerosis, arterial occlusive disorders,thrombosis, coronary rest stenosis, angina pectoris, myocardialinfarction, heart failure, ischemic heart disorders, hypertension,pulmonary hypertension, asthma, intermittent claudication and diabeticcomplications.

[0014] Accordingly, it is an object of the invention to identifycompounds which increase the concentration of cGMP in penile tissuethrough the inhibition of phosphodiesterases, specifically PDEV. It isanother object of the invention to identify compounds which are usefulfor the treatment of sexual dysfunction, particularly erectiledysfunction and/or impotence in male animals and sexual dysfunction infemale animals. Still another object of the invention is to identifymethods for treating sexual dysfunction, especially erectiledysfunction, using the compounds of the present invention.

[0015] It is another object of the invention to identify compounds whichare useful for the treatment of conditions of disorders mediated byPDEV, such as male erectile dysfunction, female sexual dysfunction,cardiovascular disorders, atherosclerosis, arterial occlusive disorders,thrombosis, coronary reststenosis, angina pectoris, myocardialinfarction, heart failure, ischemic heart disorders, hypertension,pulmonary hypertension, asthma, intermittent claudication or diabeticcomplications.

[0016] We now describe a series of pyrrolopyridinone derivatives withthe ability to inhibit phosphodiesterase type V in enzyme assays.

SUMMARY OF THE INVENTION

[0017] The present invention provides novel pyrrolopyridinone derivativecompounds useful as phosphodiesterase inhibitors. More particularly, thepresent invention is directed to compounds of the general formula (I) or(II):

[0018] wherein

[0019] R¹ is selected from the group consisting of hydrogen, carboxy,—C(O)—C₁-C₆alkyl, —C(O)—C₁-C₆alkoxy, —C(O)—NH—C₁-C₆alkyl-NH₂,—C(O)—NH—C₁-C₆alkyl-NHR^(A), —C(O)—NH—C₁-C₆alkyl-N(R^(A))₂, —C(O)—NH₂,—C(O)—NHR^(A), —C(O)—N(R^(A))₂, —C₁-C₆alkyl-NH₂, —C₁-C₆alkyl-NHR^(A),—C₁-C₆alkyl-N(R^(A))₂, —NH—C₁-C₆alkyl-N(R^(A))₂;

[0020] where each R^(A) is independently selected from the groupconsisting of C₁-C₆alkyl, aryl, C₁-C₆aralkyl and heteroaryl, where thearyl, aralkyl or heteroaryl may be optionally substituted with one tothree R^(B);

[0021] where each R^(B) is independently selected from the groupconsisting of halogen, nitro, cyano, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆alkylcarbonyl, carboxyC₁-C₆alkyl, C₁-C₆alkylsulfonyl,trifluoromethyl, amino, di(C₁-C₆alkyl)amino, acetylamino,carboxyC₁-C₆alkylcarbonylamino, hydroxyC₁-C₆alkylamino, NHR^(A)andN(R^(A))₂;

[0022] R² is selected from the group consisting of C₅-C₁₀alkyl(optionally substituted with one to three substituents independentlyselected from halogen, hydroxy, nitro, amino, NHR^(A) or N(R^(A))₂),aryl (optionally substituted with one to three substituentsindependently selected from R^(C)), cycloalkyl (optionally substitutedwith one to three substituents independently selected from R^(A)),heteroaryl (optionally substituted with one to three substituentsindependently selected from R^(C)), and heterocycloalkyl (optionallysubstituted with one to three substituents independently selected fromR^(C));

[0023] where R^(C) is selected from the group consisting of halogen,nitro, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, NH₂, NH(C₁-C₆alkyl) and N(C₁-C₆alkyl)₂;

[0024] R³ is selected from the group consisting of hydrogen, C₁-C₆alkyl,C₁-C₆alkylcarbonyl, C₂-C₆alkenylcarbonyl and C₂-C₆alkynylcarbonyl;

[0025] b is an integer from 0 to 4;

[0026] R⁴ is independently selected from the group consisting ofhalogen, hydroxy, carboxy, oxo, nitro, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆alkoxycarbonyl, trifluoromethyl, phenyl (wherein the phenyl groupmay be optionally substituted with one to three substituentsindependently selected from R^(D)), phenylsulfonyl, naphthyl,C₁-C₆aralkyl, —O-aralkyl, (wherein the aralkyl group may be optionallysubstituted with one to three substituents independently selected fromR^(D)), heteroaryl (wherein the heteroaryl may be optionally substitutedwith one to three substituents independently selected from R^(D)),heterocycloalkyl, NH₂,

[0027] where each R^(D) is independently selected from halogen, hydroxy,carboxy, oxo, C₁-C₄alkyl, C₁₋₄alkylthio, hydroxyC₁₋₄alkyl, C₁-C₄alkoxy,C_(1-C) ₄alkyoxycarbonyl, C₁-C₄alkylcarbonyl, trifluoromethyl,trifluoromethoxy, NH₂, NHR^(A), N(R^(A))₂, C(O)N(R^(A))₂, acetylamino,nitro, cyano, formyl, C₁-C₆alkylsulfonyl, carboxyC₁-C₆alkyl and aralkyl;

[0028] c is an integer from 0to 4;

[0029] R⁵ is independently selected from the group consisting ofhalogen, nitro, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, —NH₂, —NHR^(A),—N(R^(A))₂, —OR^(A), —C(O)NH₂, —C(O)NHR^(A), —C(O)N(R^(A))₂,—NHC(O)R^(A), —SO₂NHR^(A), SO₂N(R^(A))₂, where R^(A) is as definedabove, phenyl (optionally substituted with one to three substituentsindependently selected from R^(B)), heteroaryl (optionally substitutedwith one to three substituents independently selected from R^(B)) andheterocycloalkyl (optionally substituted with one to three substituentsindependently selected from R^(B));

[0030] a is an integer from 0 to 1;

[0031] Y selected from the group consisting of —C₁-C₆alkyl-, —C(O)—,—(C₁-C₆alkyl)carbonyl-, —(C₂-C₆alkenyl)carbonyl-,—(C₂-C₆alkynyl)carbonyl-, -carbonyl(C₁ -C₆alkyl)-,-carbonyl(C₂-C₆alkenyl)-, —C(O)O—(C₁-C₆alkyl)-, —C(S)—, —SO₂—,—(C₁-C₆alkyl)sulfonyl-, -sulfonyl(C₁-C₆alkyl)-, —C(O)NH—,—C(O)NH—(C₁-C₆alkyl)-, —C(O)(C₃-C₇cycloalkyl)- and—(C₃-C₇cycloalkyl)-C(O)—;

[0032]  is selected from the group consisting phenyl, furyl, thienyl andpyrrolyl;

[0033] is selected from the group consisting of aryl, heteroaryl,cycloalkyl and heterocycloalkyl;

[0034] provided that when R¹ is hydrogen, R³ is hydrogen, b is 0, c is0, a is 1,

[0035] Y is —CH₂—,

[0036]  is phenyl and

[0037]  is phenyl, then R² is not trimethoxyphenyl, (i.e. the compoundis not1,2,3,4-tetrahydro-2-(phenylmethyl)-3-(3,4,5-trimethoxyphenyl)-9H-pyrrolo[3,4-b]quinolin-9-one);

[0038] and pharmaceutically acceptable salts thereof.

[0039] Illustrative of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. An illustration of the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. Illustrating theinvention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier.

[0040] Exemplifying the invention is a method of treating a conditionselected from the group consisting of male erectile dysfunction (ED),impotence, female sexual dysfunction, female sexual arousal dysfunction,female sexual dysfunction related to blood flow and nitric oxideproduction in the tissues of the vagina and clitoris, premature labor,dysmenorrhea, cardiovascular disorders, atherosclerosis, arterialocclusive disorders, thrombosis, coronary rest stenosis, anginapectoris, myocardial infarction, heart failure, ischemic heartdisorders, hypertension, pulmonary hypertension, asthma, intermittentclaudication and diabetic complications in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

[0041] An example of the invention is a method for increasing theconcentration of cGMP in penile tissue through the inhibition ofphosphodiesterases, specifically PDEV, in a male subject in need thereofcomprising administering to the subject an effective amount of any ofthe compounds or pharmaceutical compositions described above.

[0042] Further exemplifying the invention is a method of producingendothelial-dependent vasorelaxation by potentiating the increases inintracellular cGMP induced by nitric oxide in a subject in need thereofcomprising administering to the subject an effective amount of any ofthe compounds or pharmaceutical compositions described above.

[0043] An example of the invention is the use of any of the compoundsdescribed above in the preparation of a medicament for: (a) treatingsexual dysfunction, especially male erectile dysfunction, (b) treatingimpotence, (c) increasing the concentration of cGMP in penile tissuethrough inhibition of phosphodiesterase, especially PDEV and/or (d)treating a condition selected from the group consisting of prematurelabor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterialocclusive disorders, thrombosis, coronary reststenosis, angina pectoris,myocardial infarction, heart failure, ischemic heart disorders,hypertension, pulmonary hypertension, asthma, intermittent claudicationand diabetic complications in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention provides novel pyrrolopyridinonederivatives useful for the treatment of sexual dysfunction, particularlymale erectile dysfunction (ED). Although the compounds of the presentinvention are useful primarily for the treatment of male sexualdysfunction or erectile dysfunction, they may also be useful for thetreatment of female sexual dysfunction, for example female sexualarousal dysfunction, female sexual dysfunction related to blood flow andnitric oxide production in the tissue of the vagina and clitoris, and ofpremature labor and dysmenorrhea.

[0045] More particularly, the compounds of the present invention are ofthe formula (I) or (II):

[0046] wherein all variables are as defined above, and pharmaceuticallyacceptable salts thereof.

[0047] Preferably, R¹ is hydrogen.

[0048] In an embodiment of the present invention R² is selected from thegroup consisting of phenyl (optionally substituted with one to twosubstituent selected from halogen, nitro, cyano, C₁-C₃alkyl,C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, NH₂, NH(C₁-C₃alkyl) orN(C₁-C₃alkyl)₂), heteroaryl and heterocycloalkyl. Preferably, R² isselected from the group consisting of 3,4-methylenedioxyphenyl,3,4-dimethoxyphenyl, 5-(2,3-dihydrobenzofuryl),3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 5-benxofuryl, 5-indanyl and3-thienyl. More preferably, R² is selected from the group consisting of3,4-methylenedioxyphenyl, 5-(2,3-dihydrobenzofuryl),3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 3-thienyl, 5-indanyl and5-benzofuryl. More preferably still, R² is selected from the groupconsisting of 3,4-methylenedioxyphenyl, 5-(2,3-dihydrobenzofuryl),3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 3-thienyl, 5-indanyl and5-benzofuryl. Most preferably, R² is selected from the group consistingof 3,4-methylenedioxyphenyl, and 5-(2,3-dihydrobenzofuryl).

[0049] Preferably, R³ is selected from the group consisting of hydrogenand C₁-C₄alkyl. More preferably, R³ is selected from the groupconsisting of hydrogen and methyl. Most preferably, R³ is hydrogen.

[0050] Preferably, b is an integer from 0 to 4. More preferably b is ininteger from 0 to 1.

[0051] In an embodiment of the present invention, R⁴ is selected fromthe group consisting of halogen, hydroxy, carboxy, oxo, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃alkoxycarbonyl, phenyl (wherein the phenyl may beoptionally substituted with one to two substituents selected fromhydroxy, carboxy, C₁-C₄alkyl, C₁₋₄alkylthio, hydroxyC₁₋₄alkyl,C₁-C₄alkoxy, C₁-C₄alkyoxycarbonyl, C(O)N(R^(A))₂, trifluoromethyl,trifluoromethoxy, amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, nitro,cyano or formyl), O-aralkyl, heteroaryl (wherein the heteroaryl may beoptionally substituted with one to two substituents selected fromhydroxy, carboxy, oxo, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyoxycarbonyl,C(O)N(R^(A))₂, trifluoromethyl, trifluoromethoxy, amino, nitro,C₁-C₃alkylcarbonyl or C₁₋₄aralkyl), heterocycloalkyl,

[0052] Preferably, R⁴ is selected from the group consisting of bromo,hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl,3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl,4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl,4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-cyanophenyl,4-aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl,4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, N-oxy-2-pyridinyl, 3-thienyl, 2-furyl, 1-imidazolyl,5-(1-benzyl-2-methylimidazolyl), 5-(1,2-dimethylimidazolyl),5-(1-methylimidazoly),

[0053] 5-(1-benzylimidazolyl), 3,4-methylenedioxyphenyl,

[0054] More preferably, R⁴ is selected from the group consisting of5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl,3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl,4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl,3-trifluoromethylphenyl, 4-aminophenyl, 4-dimethylaminophenyl,3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furyl, 3-thienyl,N-oxo-2-pyridinyl, 1-imidazolyl, 5-(1-benzyl-2-methylimidazolyl),5-1,2-dimethylimidazolyl), 3,4-methylenedioxyphenyl,

[0055] More preferably still, R⁴ is selected from the group consistingof 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl,3-hydroxymethylphenyl, 4-hydroxymethyphenyl, 4-carboxyphenyl,4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl,3-trifluoromethylphenyl, 4-aminophenyl, 4-dimethylaminophenyl,3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-thienyl,2-furyl, 1-imidazolyl, 5-(1-benzyl-2-methylimidazolyl),5-(1,2-dimethylimidazolyl), 3,4-methylenedioxyphenyl,

[0056] More preferably still, R⁴ is selected from the group consistingof 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl,4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl,3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,N-oxo-2-pyridinyl, 3-thienyl, 5-(1-benzyl-2-methylimidazolyl),5-(1,2-dimethylimidazolyl),

[0057] and

[0058] Most preferably, R⁴ is selected from the group consisting ofhydroxy, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-methoxycarbonyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 2-pyridinyl,3-pyridinyl,

[0059] and

[0060] In a preferred embodiment c is 0. In another preferred embodimenta is an integer from 0 to 1.

[0061] In an embodiment of the present invention, Y is selected from thegroup consisting of —C₁-C₄alkyl-, —C(S)—, —C(O)—, —C(O)O—(C₁-C₄alkyl)-,—C(O)—(C₁-C₄alkyl)-, —C(O)—(C₂-C₄alkenyl)-, C(O)—(C₃-C₇cycloalkyl)- and—C(O)NH—(C₁-C₃alkyl)-. Preferably, Y is selected from the groupconsisting of —CH₂—, —C(S)—, —C(O)—, —C(O)O—CH₂—, —C(O)—CH₂CH₂—,—C(O)—CH═CH—, —C(O)NH—CH₂—, —C(O)-cyclopropyl and —C(O)CH₂—. Morepreferably, Y is selected from the group consisting of —C(O)—,—C(O)O—CH₂—, —C(O)—CH₂CH₂—, —C(O)—CH═CH—, and —C(O)-cyclopropyl. Morepreferably still, Y is selected from the group consisting of —C(O)—,—C(O)O—CH₂— and —C(O)—CH═CH—. Most preferably, Y is selected from thegroup consisting of —C(O)— and —C(O)O—CH₂—;

[0062] Preferably,

[0063]  is phenyl;

[0064] In an embodiment of the present invention,

[0065]  is selected from the group consisting of phenyl, heteroaryl andheterocycloalkyl. Preferably,

[0066]  is selected from the group consisting of phenyl, 2-furyl,2-benzo(b)furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-imidazolyl, 2-imidazolyl, 2-thiazolyl, and2-oxa-bicyclo[2.2.1]heptanyl. More preferably,

[0067]  is selected from the group consisting of phenyl, 2-furyl,2-benzo(b)furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyland 2-thiazolyl. Most preferably,

[0068]  is selected from the group consisting of 2-furyl,2-benzo(b)furyl, 4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl.

[0069] The term “halogen” shall include iodine, bromine, chlorine andfluorine.

[0070] The term “alkyl”, whether used alone or as part of a substituentgroup, shall mean straight or branched chain alkanes of one to tencarbon atoms, or any number within this range. For example, alkylradicals include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl,2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl. Similarly, alkenyland alkynyl groups include straight and branched chain alkenes andalkynes having two to ten carbon atoms, or any number within this range.

[0071] The term “alkoxy” shall denote an oxygen ether radical of theabove described straight or branched chain alkyl group. For example,alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy,sec-butoxy, tert-butoxy, and the like.

[0072] The term “aryl” indicates an aromatic group such as phenyl,naphthyl, and the like.

[0073] The term “aralkyl” denotes an alkyl group substituted with anaryl group For example, benzyl, phenylethyl, and the like. Similarly,the term “aralkenyl” denotes an alkenyl group substituted with an arylgroup, for example phenylethylenyl, and the like.

[0074] The term “heteroaryl” as used herein represents a stable five orsix membered monocyclic aromatic ring system containing one to threeheteroatoms independently selected from N, O or S; and any nine or tenmembered bicyclic aromatic ring system containing carbon atoms and oneto four heteroatoms independently selected from N, O or S. Theheteroaryl group may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of heteroarylgroups include, but are not limited to pyridinyl, pyrimidinyl, thienyl,furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrazinyl, pyrrolyl,thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl,benzothienyl, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, purinyl. Preferred heteroaryl groups include pyrimidinyl,pyridinyl, furyl, imidazolyl, benzofuryl and thiazolyl.

[0075] The term “cycloalkyl” as used herein represents a stable three toeight membered monocyclic ring structure consisting of saturated carbonatoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

[0076] The term “heterocycloalkyl” represents a stable saturated orpartially unsaturated, three to eight membered monocyclic ring structurecontaining carbon atoms and one to four, preferably one to two,heteroatoms independently selected from N, O or S; and any stablesaturated, partially unsaturated or partially aromatic, nine to tenmembered bicyclic ring system containing carbon atoms and one to fourheteroatoms independently selected from N, O or S. The heterocycloalkylmay be attached at any carbon atom or heteroatom which results in thecreation of a stable structure. Suitable examples of heterocycloalkylgroups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,morpholinyl, dithianyl, trithianyl, dioxolanyl, dioxanyl,thiomorpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,2,3-dihydrobenzo-[1,4]-dioxin-6-yl, 2,3-dihydro-furo[2,3-b]pyridinyl,1,2-(methylenedioxy)cyclohexane, indanyl, 2-oxa-bicyclo[2.2.1]heptanyl,and the like. Preferred heterocycloalkyl groups include piperidinyl,pyrrolidinyl, morpholinyl, indanyl, 2-oxa-bicyclo[2.2.1]heptanyl,3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and2,3-dihydrobenzo-[1,4]-dioxin-6-yl.

[0077] As used herein, the notation “*” shall denote the presence of astereogenic center.

[0078] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein. It isfurther intended that when b or c is >1, the corresponding R⁴ or R⁵substituents may be the same or different.

[0079] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0080] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆ alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

[0081] The term “sexual dysfunction” as used herein, includes malesexual dysfunction, male erectile dysfunction, impotence, female sexualdysfunction, female sexual arousal dysfunction and female sexualdysfunction related to blood flow and nitric oxide production in thetissues of the vagina and clitoris.

[0082] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0083] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0084] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0085] For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

[0086] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

[0087] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0088] Abbreviations used in the specification, particularly the Schemesand Examples, are as follows: BINAP =(R)-(+)-2,2′-Bis(diphenylphosphino)- 1,1′-binaphthyl Cmpd = Compound DBU= 2,3,4,6,7,8,9,10-octahydro- pyrimido[1,2-a]azepine DCC =1,3-Dicyclohexylcarbodiimide DCM = Dichloromethane DEAD = Diethyldiazenedicarboxylate DIPEA = Diisopropylethylamine DMAP =N,N′-Dimethyl-4-pyridinamine DMF = N,N′-Dimethylformamide DMSO =Dimethyl sulfoxide dppp = 1,3-Bis(diphenylphosphino)propane EDTA =Ethylenedinitrilotetracetic acid EtOAc = Ethyl Acetate EtOH = EthanolEt₃N = Triethylamine Fmoc-NCS = [(9H-fluoren-9-ylmethoxy)carbonyl]-thiocyanate HEPES = 2-[4-(2-hydroxyethyl)-piperazinyl]-ethanesulfonic acid HPLC = High Pressure Liquid Chromatography ID # =Compound Identification Number KOt-Bu = Potassium t-butoxide MeOH =Methanol mCPBA = 3-Chloroperoxybenzoic Acid NaOt-Bu = Sodium t-butoxiden-Bu = n-Butyl NMP = N-methyl-2-pyrrolidinone Pd₂dba₃ =Tris(dibenzylidene acetone) dipalladium(0) Pd(dppf)(OAc)₂ =1,1′-bis(diphenylphosphino) ferrocene palladium diacetate Pd(OAc)₂ =Palladium (II) Acetate Pd(dppf)Cl₂ = 1,1′-Bid(diphenylphosphino)ferrocene palladium (II) dichloride Pd(PPh₃)₄ or = Palladiumtetrakis(triphenyl Pd(Ph₃P)₄ phosphine) Ph = Phenyl PMSF =Phenylmethanesulfonyl fluoride PPh₃ = Triphenyl phosphine PyBrOP =Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate TEA =Triethylamine TFA = Trifluoroacetic Acid THF = Tetrahydrofuran TLC =Thin Layer Chromatography TsOH = p-Toluenesulfonic acid SNP = SodiumNitroprusside

[0089] Compounds of formula (I) wherein R³ is hydrogen, may be preparedaccording to two alternative processes from a suitably substitutedcompound of formula (III):

[0090] wherein R¹, R², R⁵ and c are as previously defined, which isselected and used as a starting reagent.

[0091] The compound of formula (III) is a known compound or compoundprepared by known methods, for example according to the process outlinedin Scheme 1 below:

[0092] Accordingly, a compound of formula (IV), a known compound orcompound produced by known methods, is reacted with a suitablysubstituted aldehyde of formula (V), in an organic solvent such as DCM,THF, toluene, and the like, in the presence of an acid catalyst such asTFA, tosic acid, and the like, to produce the corresponding compound offormula (III).

[0093] Generally, in the first of two alternative processes, thecompounds of formula (I) may be prepared by reacting a suitablysubstituted compound of formula (III) to produce the correspondingsubstituted pyrrolopyridinone derivative. In the second process of twoalternative processes, the compounds of formula (I) may be prepared byinitially reacting a suitably substituted compound of formula (III) toform a tricyclic pyrrolopyridinone moiety, followed by introduction ofadditional substituents. This second process is particularly preferredfor preparation of compounds of formula (I) wherein Y is —C(S), —C(O)O—Ror —C(O)R^(A).

[0094] More specifically, compounds of formula (I) wherein R³ ishydrogen, may be prepared from a suitably substituted compound offormula (III) according to the processes outlined in Scheme 2.

[0095] In the first process, a suitably substituted compound of formula(III) is reacted with a suitably substituted compound of formula (VI),wherein X is halogen, hydroxy, tosylate, mesylate, p-nitrophenoxide orthe like, preferably X is halogen, hydroxy or p-nitrophenoxide, in anorganic solvent, such as DMF, THF, DCM, toluene, and the like, toproduce the corresponding compound of formula (VII). For compounds offormula (I) wherein (Y)_(a) is (Y)₀ (i.e. where a is 0 such that Y isabsent), the reaction mixture is preferably heated to a temperature ofgreater than or equal to about 100° C. For compounds of formula (I)wherein (Y)_(a) is (Y)₀ (i.e. where a is 0 such that Y is absent) and

[0096] is pyridinyl, the reaction mixture is preferably catalyzed at atemperature in the range of about 30-120° C. with a catalyst such asPd(OAc)₂, Pd₂dba₃, Pd(dppf)Cl₂, and the like, in an organic solvent suchas 1,4-dioxane, THF, DMF, DCM, toluene, and the like, to yield thecorresponding compound of formula (VII).

[0097] The compound of formula (VII) is next reacted with an oxidizingagent such as NalO₄, KO₂, singlet oxygen, oxygen gas, ozone, and thelike, preferably oxygen gas applied at about atmospheric pressure, toproduce the corresponding pyrrolopyridinone derivative of formula (Ia).When the oxidizing agent is oxygen gas, the reaction is carried out inthe presence of a base such as sodium hydride, potassium-t-butoxide, andthe like.

[0098] In the alternative process outlined in Scheme 2, a suitablysubstituted compound of formula (III) is first reacted with an oxidizingagent such as NalO₄, KO₂, singlet oxygen, oxygen gas, ozone, and thelike, preferably oxygen gas applied at about atmospheric pressure, toproduce the corresponding compound of formula (VIII). When the oxidizingagent is oxygen gas, the reaction is carried out in the presence of abase such as sodium hydride, potassium-t-butoxide, and the like.

[0099] The compound of formula (VIII) is next reacted with a suitablysubstituted compound of formula (VI), where X is halogen, hydroxy,tosylate, mesylate, p-nitrophenoxide or the like, preferably X ishalogen, hydroxy or p-nitrophenoxide, in an organic solvent such as DMF,THF, DCM, toluene, and the like, optionally in the presence of acatalyst such as DMAP, to produce the corresponding substitutedpyrrolopyridinone of formula (Ia). For compounds of formula (I) wherein(Y)_(a) is (Y)₀ (i.e. where a is 0 such that Y is absent), the reactionmixture is preferably heated to a temperature of great than or equal toabout 50° C. For compounds of formula (VIII) wherein (Y)_(a) is (Y)₀(i.e. where a is 0 such that Y is absent) and

[0100] is pyridinyl, the reaction mixture is preferably catalyzed at atemperature in the range of about 30-120° C. with catalyst such asPd(OAc)₂, Pd₂dba₃, Pd(dppf)Cl₂, and the like, in an organic solvent suchas 1,4-dioxane, THF, DMF, DCM, toluene, and the like, to yield thecorresponding compound of formula (Ia).

[0101] Alternatively, for compounds of formula (I) wherein (Y)_(a) isCH₂ and

[0102] is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl, the compound of formula (VIII) may be preparedby reacting a compound of formula (Ia) with hydrogen gas, where thehydrogen gas is applied at a pressure in the range of about atmosphericpressure to about 80 p.s.i., in the presence of a catalyst such as Pd,Pt, palladium on carbon, and the like, in an organic solvent such asmethanol, ethanol, ethyl acetate, and the like. The compound of formula(VIII) may then be further functionalized as described above.

[0103] Compounds of formula (I) wherein b is 1 (i.e. wherein the grouprepresented by

[0104] is substituted with one R⁴ substituent) may be prepared from asuitably substituted compound of formula (III) according to threealternative processes.

[0105] In the first process, a suitably substituted compound of formula(III) is initially converted to the corresponding pyrrolopyridinoneaccording to the process outlined in Scheme 2, followed by two stepsubstitution at the pyrrole nitrogen, as outlined in Scheme 3.

[0106] Specifically, the compound of formula (VIII) is reacted with asuitably substituted compound of formula (IX), wherein X is a halogen,in the presence of a base such as TEA, DIPEA, and the like, in anorganic solvent such as DMF, DCM, THF, and the like, preferably at atemperature in the range of about 20 to about 150° C., to yield thecorresponding compound of formula (X).

[0107] The compound of formula (X) is reacted with a suitablysubstituted boronic acid of formula (XI) or a suitably substitutedtributyl-stannane of formula (XII), to yield the corresponding compoundof formula (Ib). When selected reagent is a boronic acid of formula(XI), the compound of formula (X) is reacted in an organic solvent suchas DMF, THF, dioxane, and the like, in the presence of a catalyst suchas Pd(Ph₃P)₄, Pd(dppf)(OAc)₂, and the like, preferably at a temperaturein the range of about 80-150° C. When the selected reagent is atributyl-stannane of formula (XII), the compound of formula (X) isreacted in a solvent such as DMF, in the presence of a catalyst such asPd(dppf)(OAc)₂.

[0108] In the second process, the compound of formula (III) is initiallysubstituted with a bromo-substituted

[0109] then converted to the corresponding pyrrolopyridinone, and thenfurther substituted at the

[0110] as shown in Scheme 4.

[0111] More particularly, a suitably substituted compound of formula(III) is reacted with a suitably substituted compound of formula (XIII),wherein X is a halogen, in the presence of a base such as TEA, DIPEA,and the like, in an organic solvent such as DMF, toluene, and the like,preferably at a temperature in the range of about 100 to about 150° C.,to yield the corresponding compound of formula (XIV).

[0112] The compound of formula (XIV) is reacted with an oxidizing agentsuch as NalO₄, KO₂, singlet oxygen, oxygen gas, ozone, and the like,preferably oxygen gas applied at atmospheric pressure, to produce thecorresponding compound of formula (XV).

[0113] The compound of formula (XV) is reacted with a suitablysubstituted boronic acid of formula (XI) or a suitably substitutedtributyl-stannane of formula (XII), to yield the corresponding compoundof formula (Ic). When selected reagent is a boronic acid of formula(XI), the compound of formula (XV) is reacted in an organic solvent suchas DMF, dioxane, water, and the like, in the presence of a catalyst suchas Pd(Ph₃P)₄, Pd(dppf)(OAc)₂, and the like, preferably at a temperaturein the range of about 80 to about 160° C. When the selected reagent is atributyl-stannane of formula (XII), the compound of formula (XV) isreacted in a solvent such as DMF, TEA, and the like, in the presence ofa catalyst such as Pd(dppf)(OAc)₂.

[0114] In the third process, the compound of formula (III) is initiallysubstituted with a bromo-substituted

[0115] further substituted at the

[0116] with the R⁴ substituent, and then converted to the correspondingpyrrolopyridinone, as shown in Scheme 5.

[0117] More particularly, the compound of formula (XIV) is reacted witha suitably substituted boronic acid of formula (XI) or a suitablysubstituted tributyl-stannane of formula (XII), to yield thecorresponding compound of formula (XVI). When selected reagent is aboronic acid of formula (XI), the compound of formula (XIV) is reactedin an organic solvent such as DMF, dioxane, water, and the like, in thepresence of a catalyst such as Pd(Ph₃P)₄, Pd(dppf)(OAc)₂, and the like,preferably at a temperature in the range of about 80 and about 120° C.When the selected reagent is a tributyl-stannane of formula (XII), thecompound of formula (XIV) is reacted in a solvent such as DMF, dioxane,and the like, in the presence of a catalyst such as Pd(dppf)(OAc)₂.

[0118] The compound of formula (XVI) is reacted with an oxidizing agentsuch as NalO₄, KO₂, singlet oxygen, oxygen gas, ozone, and the like,preferably oxygen gas applied at atmospheric pressure, to produce thecorresponding compound of formula (Ic).

[0119] Compounds of formula (I) wherein b is an integer selected from 2,3 and 4, (i.e. wherein the

[0120] is substituted with 2, 3 or 4 R⁴ groups) may similarly beprepared according to the processes outlined in Schemes 3, 4 and 5, withappropriate substitution of the

[0121] containing reagent with the corresponding reagent wherein the

[0122] is substituted with 2, 3 or 4 bromine groups, which brominegroups are sequentially reacted to incorporate the desired R⁴ groups.

[0123] Compounds of formula (I) wherein (Y)_(a) is C(O) may be preparedaccording to two alternative processes. In the first process, apyrrolopyridinone compound of formula (VIII) is initially substitutedwith a suitably selected carboxylic acid or acid chloride, followed byfurther substitution of the

[0124] with the R⁴ substituent, as outlined in Scheme 6.

[0125] More particularly, a suitably substituted pyrrolopyridinonecompound of formula (VIII) is reacted with a suitably substitutedcarboxylic acid or acid chloride of formula (XVIII), wherein W is OH orCl, in an organic solvent such as DMF, THF, dioxane, and the like, andwhen W is OH in the presence of a catalyst such as PyBrop, DCC, and thelike, and when W is Cl in the presence of a base such as TEA, DIPEA, andthe like, preferably at a temperature in the range of about 0 to about30° C., to yield the corresponding compound of formula (XVIII).

[0126] The compound of formula (XVIII) is reacted with a suitablysubstituted boronic acid of formula (XI), in an organic solvent such asDMF, dioxane, water, and the like, in the presence of a catalyst such asPd(Ph₃P)₄, and the like, preferably at a temperature in the range ofabout 80 to about 120° C., to yield the corresponding compound offormula (Id).

[0127] In the second process, a suitably substituted compound of formula(III) is initially converted to the corresponding pyrrolopyridinone,followed by two step substitution using a suitable selected carboxylicacid, followed by boronic acid or stannane, as outlined in Scheme 7.

[0128] More particularly, a suitably substituted compound of formula(III) is reacted with a suitably substituted carboxylic acid of formula(XVII), wherein W is halogen or hydroxy, in an organic solvent such asTEA, DIPEA, and the like, preferably at a temperature in the range ofabout 80 to about 130° C., to yield the corresponding compound offormula (XIX).

[0129] The compound of formula (XIX) is reacted with a suitablysubstituted boronic acid of formula (XI) or a suitably substitutedtributyl-stannane of formula (XII), to yield the corresponding compoundof formula (XX). When selected reagent is a boronic acid of formula(XI), the compound of formula (XIX) is reacted in an organic solventsuch as DMF, dioxane, water, and the like, in the presence of a catalystsuch as Pd(Ph₃P)₄, Pd(dppf)(OAc)₂, and the like, preferably at atemperature in the range of about 80 to about 120° C. When the selectedreagent is a tributyl-stannane of formula (XII), the compound of formula(XIX) is reacted in a solvent such as DMF, dioxane, and the like, in thepresence of a catalyst such as Pd(dppf)(OAc)₂.

[0130] The compound of formula (XX) is reacted with an oxidizing agentsuch as NalO₄, KO₂, singlet oxygen, oxygen gas, ozone, and the like,preferably KO₂, to produce the corresponding compound of formula (Id).

[0131] Compounds of formula (I), wherein R³ is other than hydrogen, andcompounds of formula (II), may be prepared according to the processoutlined in Scheme 8.

[0132] More specifically, a compound of formula (Ia) is reacted with asuitably substituted compound of formula (XXI), where X is halogen,hydroxy, tosylate, mesylate, and the like, preferably X is halogen, inan organic solvent such as THF, DMF, dichloromethane, toluene, and thelike, preferably THF or DMF, to yield a mixture of the correspondingsubstituted compound of formula (Ie) and the corresponding substitutedcompound of formula (II). When in the compound of formula (XXI), X ishalogen, the reaction is preferably carried out in the presence of anorganic or inorganic base such as triethylamine, diisopropylethylamine,potassium carbonate, sodium hydride, sodium hydroxide and the like.

[0133] The compounds of formula (Ie) and (II) are preferably separatedby known methods such as recrystallization, column chromatography, HPLC,and the like.

[0134] Compounds of formula (VII) wherein Y_(a) is Y₀ (i.e. wherein Y isabsent) and

[0135] is 2-(4-substituted)thiazolyl, may be prepared according to aprocess as outlined in Scheme 9.

[0136] Accordingly, a suitably substituted compound of formula (III) isreacted with Fmoc-NCS, in an organic solvent such as DCM, DMF, THF, andthe like, preferably at room temperature, to produce the correspondingcompound of formula (XXII).

[0137] The compound of (XXII) is reacted with 20% piperidine, in analcohol such as methanol, ethanol, and the like, to produce thecorresponding amine of formula (XXII).

[0138] The amine of formula (XXIII) is reacted with a suitablysubstituted α-halo methyl ketone of formula (XXIV), in the presence ofan organic solvent or mixture such as DMF, ethanol:dioxane, and thelike, in the presence of a base such as TEA, DIPEA, and the like,preferably at a temperature of about 70° C., to produce thecorresponding compound of formula (VIIa).

[0139] Specific diastereomers of the compounds of formula (I), moreparticularly compounds of formula (I) wherein R¹ is hydrogen and anR-configuration at the chiral center of the R² bond to thepyrrolopyridinone is desired, may be prepared according to the processoutlined in Scheme 10.

[0140] Accordingly, a suitably substituted compound of formula (XXV), aknown compound or compound prepared by known methods, wherein R¹ ishydrogen and Ar is an aryl group, preferably naphthyl, more preferably1-naphthyl, is reacted with a suitably substituted aldehyde, a compoundof formula (XXVI), in an organic solvent such as p-xylene, o-xylene,toluene, DCM, and the like, at a temperature in the range of about25-270° C., under aprotic or protic conditions, to yield a mixture ofthe corresponding diastereomers, compounds of formula (XXVII) and(XXVIII).

[0141] The R-diastereomer, the compound of formula (XXVII) is separatedfrom the compound of formula (XXVIII) by recrystallization or silica gelchromatography.

[0142] The compound of formula (XXVII) (the S-diastereomer) is convertedto the desired R-diastereomer, the compound of formula (XXVIII), bystirring the compound of formula (XXVII) in an acid such as TFA, HCI,TsOH, and the like, in the presence of an organic solvent such asCH₂Cl₂, DCM, 1 m4-dioxane, and the like, to yield the desiredR-diastereomer, the compound of formula (XXVIII).

[0143] The compound of formula (XXVIII) is reacted with an oxidizingagent such as oxygen gas, singlet oxygen, KO₂, NalO₄, ozone, and thelike, preferably oxygen gas at about atmospheric pressure, to yield thecorresponding compound of formula (XXIX). When the oxidizing agent isoxygen gas, the reaction is carried out in the presence of a base suchas sodium hydride, potassium-t-butoxide, and the like, in an organicsolvent such as DMF, DMSO, NMP, and the like.

[0144] The compound of formula (XXIX) is reacted with a reducing agentsuch as hydrogen gas, in the presence of a catalyst such as palladium oncarbon, in a polar solvent such as methanol, ethanol, and the like, toyield the corresponding compound of formula (VIIIa).

[0145] The compound of formula (VIIIa) may then be further reacted toyield the corresponding compound of formula (I) according to the processoutlined in Scheme 3 above.

[0146] For compounds of formula (I), wherein R¹ is other than hydrogen,a second chiral center will exist at the bond of the R¹ group to thepyrrolopyridinone. If a specific orientation of the R¹ group is presentin the starting reagent, the compound of formula (XXV) in Scheme 10above, its orientation will impact the conversion of diastereomers.

[0147] Where the processes for the preparation of the compoundsaccording to the invention give rise to a mixture of stereoisomers,these isomers may be separated by conventional techniques such aspreparative chromatography. The compounds may be prepared in racemicform, or individual enantiomers may be prepared by enantioselectivesynthesis, by resolution or from enantiomerically enriched reagents. Thecompounds may, for example, be resolved into their component enantiomersby standard techniques, such as the formation of diastereomeric pairs bysalt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters, amides or amines, followed by chromatographic separation andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using a chiral HPLC column.

[0148] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

[0149] The utility of the compounds to treat sexual dysfunction can bedetermined according to the procedures described in Example 95, 96 and97 herein.

[0150] The present invention therefore provides a method of treatingsexual dysfunction, more particularly male erectile dysfunction in asubject in need thereof which comprises administering any of thecompounds as defined herein in a quantity effective to treat ED. Thecompound may be administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral. The quantity ofthe compound which is effective for treating ED is between 0.01 mg perkg and 20 mg per kg of subject body weight.

[0151] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 1 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

[0152] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0153] The method of treating sexual dysfunction, more particularly maleerectile dysfunction described in the present invention may also becarried out using a pharmaceutical composition comprising any of thecompounds as defined herein and a pharmaceutically acceptable carrier.The pharmaceutical composition may contain between about 1 mg and 1000mg, preferably about 1 to 200 mg, of the compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixers,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

[0154] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0155] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0156] The liquid forms may include suitably flavored suspending ordispersing agents such as the synthetic and natural gums, for example,tragacanth, acacia, methyl-cellulose and the like. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations which generally contain suitable preservatives are employedwhen intravenous administration is desired.

[0157] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phophatidylcholines.

[0158] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0159] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of sexual dysfunction, more particularly maleerectile dysfunction is required.

[0160] The daily dosage of the products may be varied over a wide rangefrom 1 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.1 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.1mg/kg to about 3 mg/kg of body weight per day.

[0161] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[0162] The following Examples are set forth to aid in the understandingof the invention, and are not intended and should not be construed tolimit in any way the invention set forth in the claims which followthereafter. Unless otherwise indicated, ¹H NMRs were run on a Brukerinstrument.

EXAMPLE 11-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline

[0163] To a solution of the1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (preparedaccording to the process as disclosed in WO97/43287, Intermediate 7,page 24) (7.37 g, 25 mmol) in dry DMF (25 mL) was added triethylamine(3.52 mL, 25 mmol) and benzyl bromide (3.00 mL, 25 mmol). The mixturewas stirred at ambient temperature overnight and added dropwise to asolution of sodium hydroxide (25 mmol) in water (200 mL). A precipitatewas formed, collected by vacuum filtration, washed with water (2×50 mL),and dried in vacuo overnight to yield the product as a freely flowingpale yellow powder.

[0164] MS (m/z) 383 (MH⁺)

[0165]¹H NMR (CDCl₃) δ2.57-2.89 (series of m, 3H), 3.18-3.23 (m, 1H),3.33 (d, J=13.7 Hz, 1H), 3.63 (d, J=13.7 Hz, 1H), 4.55 (s, 1H), 5.94(nd, J=2.2 Hz, 2H), 6.77-7.52 (series of m, 13H).

EXAMPLE 1A(R)-1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline

[0166] Following the procedure as described in Example 1,(R)-1-(3,4,-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline wasreacted to produce the title compound.

[0167] MS (m/z) 383 (MH⁺)

EXAMPLE 21-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline

[0168] The title product was prepared according to the process describedin Example 1 using1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline as thestarting reagent.

[0169] MS (m/z) 381 (MH⁺)

[0170]¹H NMR (CDCl₃) δ2.59-2.90 (series of m, 3H), 3.13-3.24 (m, 3H),3.33 (d, J=13.5 Hz, 1H), 3.93 (d, J=13.5 Hz, 1H), 4.56 (t, J=8.6 Hz,2H), 6.75 (d, J=8.1 Hz, 1H), 7.05-7.35 (series of m, 10H), 7.49-7.52 (m,1H)

EXAMPLE 2A(R)-1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline

[0171] Following the procedure as described in Example 2,(R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline wasreacted to produce the title compound.

[0172] MS (m/z) 381 (MH⁺)

[0173] [α}=−56.9° (c=0.62, CH₃OH)

EXAMPLE 31,2,3,4-Tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#54)

[0174]1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline(0.79 g, 2.0 mmol) (prepared as in Example 1) was dissolved in dry DMF(15 mL). Potassium t-butoxide (0.56 g, 5.0 mmol) was added, followed byoxygen, bubbled in via syringe needle. The mixture was maintained atroom temperature for one hour and then poured onto a mixture of 1N HCl(5 mL), water (35 mL) and ethyl acetate (35 mL). A fluffy yellowprecipitate was collected, the organic layer removed, and the aqueoussolution extracted with ethyl acetate (15 mL). The extracted layer wasagitated and set aside overnight. The following day an additionalquantity of product (as a precipitate) was collected. Drying of thecombined solids yielded the product as a yellow powder.

[0175] MS (m/z): 397 (MH⁺)

[0176]¹H-NMR (DMSO-d6) δ3.52 (dd, J=11.9, 3 Hz, 1 H), 3.63 (d, J=13.2Hz, 1 H), 3.84 (d, J=13.2 Hz, 1 H), 3.93 (dd, J=11.9, 3 Hz, 1 H), 5.10(s, 1 H), 6.05 (nd, J=3.4 Hz, 2 H), 6.98 (s, 3 H), 7.26-7.36 (m, 6 H),7.54-7.59 (m, 2 H), 8.10 (d, J=8 Hz, 1 H), 11.42 (s, 1 H).

EXAMPLE 3A(R)-1,2,3,4-Tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#67)

[0177] Following the procedure as described in Example 3,(R)-1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolinewas reacted to produce the title compound.

[0178] MS (m/z) 397 (MH⁺)

EXAMPLE 41,2,3,4-Tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#60)

[0179]1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline(prepared as in Example 2) (3.10 g, 8.15 mmol) was dissolved in dry DMF(20 mL). Potassium t-butoxide (2.29 g, 20.38 mmol) was added, followedby oxygen, bubbled in via syringe needle. The solution was stirred for1.5 h. To the reaction mixture was added a solution of HCl in ether (10mL, 2M) and the solution dripped into rapidly stirring water. Theresulting suspension was stirred overnight. A brown solid was filteredoff and washed with water. The filtrate was neutralized with 1N NaOH,resulting in a yellow precipitate. The solid was filtered, washed withwater, dried briefly, and partially dissolved in THF/methanol. Theprecipitate solid was filtered and washed with ether to yield theproduct as a pale yellow solid.

[0180] MS (m/z) 395 (MH⁺)

[0181]¹H NMR (DMSO-d6) δ3.19 (t, J=8.7 Hz, 2H), 3.53 (d, J=11.8 Hz, 1H),3.61 (d, J=12.2 Hz, 1H), 3.82 (d, J=12.2 Hz, 1H), 3.92 (d, J=11.8 Hz,1H), 4.55 (t, J=8.7 Hz, 2H), 5.08 (s, 1H), 6.81 (d, J=8.1 Hz, 1H),7.16-7.59 (series of m, 9H), 8.10 (d, J=8.1 Hz, 1H), 11.42 (s, 1H).

EXAMPLE 4A(R)-1,2,3,4-Tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#77)

[0182] Following the procedure as described in Example 4,(R)-1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolinewas reacted to produce the title compound.

[0183] MS (m/z) 395 (MH⁺)

[0184] [α]=−110.0° (c=0.43, CH₃OH); HPLC Chiralpak OD 0.46×25 cm,0.1%DEA/MeOH, Tr=5.36 0 min.

EXAMPLE 51,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (#4)

[0185] Method A: HCl Salt

[0186] To a suspension of1,2,3,4-tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(prepared as in Example 3) (1.12 g, 2.82 mmol) in methanol (50 mL) and10% Pd/C (500 mg) was added HCl in ether solution (1.41 mL, 2N). Thereaction mixture was agitated under a hydrogen atmosphere (45 psi) in aParr apparatus for 6 h. The resulting solution was filtered throughCelite and concentration in vacuo to yield the product as a green solid.

[0187] MS (m/z) 307 (MH⁺)

[0188]¹H NMR (DMSO-d6) δ4.39-4.48 (m, 2H), 6.09 (broad s, 3H), 6.97-7.05(m, 3H), 7.40 (t, J=7.1 Hz, 1H), 7.60-7.71 (m, 2H), 8.17 (d, J=8.0 Hz,1H), 9.68 (s, 1H), 11.13 (s, 1H).

[0189] Method B: Free Base

[0190] 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline ,a known compound, (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) (15.35 g, 52.5 mmol) was dissolvedin dry DMF (90 mL). Potassium tert-butoxide (10.02 g, 89.3 mmol) wasintroduced in one portion and the suspension was stirred until a clearsolution was obtained. Oxygen gas was then passed through the solutionvia a syringe needle for 50 min. The reaction was quenched by theaddition of glacial acetic acid (5.11 mL, 89.3 mmol) and poured intodiethyl ether (1 L), which resulted in a precipitate that was collectedby filtration. The product was purified by flash chromatography (0-50%EtOH/THF) to yield the product as a yellow powder.

[0191] MS (m/z): 307 (MH⁺)

[0192]¹H-NMR (CD₃OD) δ4.18 (d, J=13.7 Hz, 1 H), 4.36 (d, J=13.7 Hz, 1H), 4.92 (broad s, 2 H), 5.43 (s, 1 H), 5.92 (s, 1H), 6.74 (s, 1 H),6.81 (s, 1 H) 7.36-7.70 (series of m, 4 H), 8.31 (d, J=8.6 Hz, 1 H).

EXAMPLE 5A(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (#48)

[0193] Following the procedure as described in Example 5, Method A,(R)-1,2,3,4-tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-onewas reacted to produce the title compound.

[0194] MS (m/z) 307 (MH⁺)

EXAMPLE 61,2,3,4-Tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt

[0195] Method A: HCl Salt

[0196] The title product was prepared according to the process describedin Example 4 with substitution of appropriate reagents.

[0197] MS (m/z) 305 (MH⁺)

[0198]¹H NMR (DMSO-d6) δ3.17-3.20 (m, 2H), 4.38-4.60 (m, 4H), 6.10 (s,1H) 6.85 (d, J=8.2 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.40(t, J=7.1 Hz, 1H), 7.61 (t, J=8.2 Hz, 1H), 7.68(d, J=7.2 Hz, 1H), 8.17(d, J=8.9 Hz, 1H), 9.71 (s, 1H), 11.17 (s, 1H).

[0199] Method B: Free Base

[0200] 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline(1.06 g, 3.64 mmol), a known compound, (prepared according to theprocess as disclosed in WO97/43287, Intermediate 10, page 25) wasdissolved in dry DMF (8 mL). Potassium tert-butoxide (829 mg, 7.38 mmol)was introduced in one portion and the suspension was stirred until aclear solution was obtained. Oxygen gas was then passed through thesolution via a syringe needle for 50 min. The reaction was quenched bythe addition of glacial acetic acid (0.42 mL, 7.34 mmol) and poured intodiethyl ether (50 mL), which resulted in a precipitate that wascollected by filtration. The product was purified by flashchromatography (0-50% MeOH/THF) to yield the product as a yellow powder.

[0201] MS (m/z): 305 (MH⁺)

[0202]¹H-NMR (CD₃OD) δ3.17 (t, J=8.7 Hz, 2H), 3.29-3.31 (m, 2 H), 4.18(d, J=12.9 Hz, 1 H), 4.38 (d, J=12.9 Hz, 1 H), 4.53 (t, J=8.7 Hz, 2 H),5.44 (s, 1 H), 6.74 (d, J=8.2 Hz, 1 H), 7.07 (d, J=8.2 Hz, 1 H), 7.13(s, 1 H), 7.40 (t, J=7.9 Hz, 1 H), 7.54 (d, J=8.3 Hz, 1 H), 7.65 (t,J=7.9 Hz, 1 H), 8.29 (d, J=8.1 Hz, 1 H).

EXAMPLE 6A(R)-1,2,3,4-Tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt

[0203] Following the procedure as described in Example 6, Method A,(R)-1,2,3,4-tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-onewas reacted to produce the title compound.

[0204] MS (m/z) 305 (MH⁺)

[0205] [α}=+39.0° (C=0.605, 1% TFA in CH₃OH)

EXAMPLE 7 (4-Pyridinyl)methyl-4-nitrophenylcarbonic acid ester

[0206] To a solution of 4-pyridinylcarbinol (50 mmol) and triethylamine(50 mmol) in dry dichloromethane (100 mL) was added a solution of4-nitrophenylchloroformate (50 mmol). The reaction mixture was stirredovernight at ambient temperature, resulting in a yellow precipitatewhich was removed by filtration, and concentrated. The semisolid residuewas treated with THF (50 mL) to form a white precipitate. Theprecipitate was collected by filtration, concentrated and purified byflash chromatography (20% THF/CHCl₃) to yield the product as an orangesolid.

[0207] MS (m/z) 275 (MH⁺)

[0208]¹H NMR (CDCl₃) δ5.33 (s, 2H), 7.36 (d, J=5.8 Hz, 2H), 7.41 (d,J=9.4 Hz, 2H), 8.30 (d, J=9.4 Hz, 2H), 8.68 (d, J=5.8 Hz, 2H).

EXAMPLE 8 6-[2-(1-Morpholino)ethoxy]-2-benzofurancarboxylic acid

[0209] A solution of 6-methoxy-2-benzofurancarboxylate methyl ester (868mg, 4.52 mmol) in dry benzene was treated with triphenylphosphine (1.18g, 4.52 mmol) and 1-(2-hydroxyethyl)-morpholine (0.72 mL, 4.57 mmol)under an argon atmosphere. DEAD (0.55 mL, 4.5 mmol) was added dropwiseto the reaction mixture, at room temperature. The solution was stirredovernight, concentrated in vacuo and the residue purified by flashchromatography (0-10% MeOH/CHCl₃).

[0210] The purified product was subjected to saponification for 3 h in a1:1 mixture of methanol and aqueous 1N NaOH (80 mL) at refluxtemperature. The reaction mixture was neutralized with concentrated HCland concentrated to yield a residue which was triturated with methanol(20 mL). The resulting salt was removed by filtration and concentratedto yield a second residue that was similarly triturated with THF. Thethird residue was dried under vacuum to yield the product as a yellowpowder.

[0211] MS (m/z) 292 (MH⁺)

[0212]¹H NMR (DMSO-d6) δ2.57 (broad s, 4H), 2.87 (t, J=5.3 Hz, 2H), 3.64(t, J=4.6 Hz, 4H), 4.23 (t, J=5.5 Hz, 2H), 6.97 (dd, J=8.7,2 Hz, 1H),7.31 (s, 1H), 7.53 (s, 1H), 7.63 (d, J=8.7 Hz, 1H).

EXAMPLE 91-(3,4-Methylenedioxyphenyl)-2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0213] To a suspension of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (27.7 g,94.8 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) in dry methanol (300 mL) was addedt-butylpyrocarbonate (25.0 g, 114 mmol). Shortly after the addition ofthe pyrocarbonate, a clear solution was formed. The solution was stirredat ambient temperature for 1 h, resulting in formation of a whiteprecipitate. The solid was collected by filtration, washed with a 1:1mixture of diethyl ether:pentane, and dried in vacuo to yield theproduct as a white solid.

[0214] MS (m/z): 415 (MNa⁺)

[0215]¹H-NMR (CDCl₃) δ1.53 (s, 9H), 2.75-3.17 (series of m, 3 H), 4.22(broad, 1 H), 5.93 (s, 2 H), 6.31 (broad, 1 H), 6.64-6.72 (m, 2 H), 6.80(s, 1 H), 7.12-7.33 (series of m, 3 H), 7.54 (d, J=7.7 Hz, 1 H), 7.93(broad, 1 H);

EXAMPLE 101-(3,4-Methylenedioxyphenyl)-2-(benzyloxycarbonyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0216] To a solution of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (9.11 g,31.1 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) in dry dichloromethane (100 mL)were added triethylamine (8.80 mL, 63.1 mmol) and dimethylaminopyridine(5 mg), followed by the dropwise addition of benzylchloroformate (4.60mL, 30.6 mmol) over a period of 30 min. The reaction mixture was stirredfor 16 h, transferred to a separatory funnel, washed with 2N HCl, brine,dried over anhydrous magnesium sulfate and concentration in vacuo. Flashchromatography yielded the product as a white solid.

[0217] MS (m/z): 425 (M−1)

[0218]¹H-NMR (CDCl₃) δ2.78-2.95 (broad m, 2 H), 3.15-3.25 (m, 1 H), 4.40(broad, 1 H), 5.14 (d, J=12.3 Hz, 1 H), 5.22 (d, J=12.3 Hz, 1H), 5.90(s, 2 H), 6.35 (broad 1 H), 6.80 (broad, 3 H), 7.09-7.35 (series of m, 8H), 7.53 (d, J=7.6 Hz, 1 H), 7.70 (broad, 1 H);

EXAMPLE 11 1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0219] To a solution of tryptamine (5.0 g, 0.0312 mol) and 3,4-dimethoxybenzaldehyde (5.7 g, 0.0312 mol) in CH₂Cl₂ (220 mL) was added TFA (4.5mL, 0.0584 mol). The deep blue solution was stirred at room temperaturefor 20 h. The reaction mixture was neutralized with NaHCO₃ (4.9 g,0.0584 mol) in H₂O (50 mL) and the organic layer washed with brine(2×100 mL). The reaction mixture was dried with MgSO₄ and the solventevaporated. Product was isolated by column chromatography (silica gel;CH₃OH:EtOAc=1:9) as a yellowish oil, which solidified slowly uponstanding at room temperature.

[0220] mp: 146-148° C.; MS (m/z) 307 (M−1), 309 (MH⁺)

[0221]¹H NMR (CDCl₃) δ2.70˜2.92 (m, 2H), 3.05 (m, 1H), 3.31 (m, 1H),3.65 (s, 3H), 3.81 (s, 3H), 5.01 (s, 1H), 6.72 (m, 2H), 7.12 (m, 3H),7.52 (m, 1H) 8.18 (s, 1H)

EXAMPLE 121-(3,4-Methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-δ-carboline

[0222] 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline(2.72 g, 9.6 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and2-chloro-5-(4-methoxyphenyl)pyrimidine (1.04 g, 4.78 mmol) were stirredin DMF (20 mL, anhydrous) at 120 ° C. for 16 h. The resulting mixturewas quenched with saturated NH₄Cl, extracted with ethyl acetate anddried with MgSO₄. The reaction mixture solvent was evaporated and theresidue purified by column chromatography (silica gel, ethylacetate:hexanes=1:2) to yield the product as a white solid.

[0223] mp: 200-202 ° C.; MS (m/z): 477 (MH⁺)

[0224]¹H-NMR (DMSO-d₆) δ2.71 (m, 2 H), 3.25 (m, 1H), 3.78 (s, 3 H), 4.93(d, J=12 Hz, 1 H), 5.99 (d, J=5 Hz, 2 H), 6.76 (d, J=8 Hz, 1 H), 6.87(d, J=8 Hz, 2 H), 7.02 (d, J=9 Hz, 2 H), 7.06 (d, J=7 Hz, 1 H), 7.11 (s,1 H), 7.31 (d, J=8 Hz, 1 H), 7.46 (d, J=8 Hz, 1 H), 7.59 (d, J=9 Hz, 2H), 8.74 (s, 2H), 11.00 (s, 1H);

EXAMPLE 131-(3,4-Methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0225] Following the same procedure as outlined in Example 12,1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.73 g,12.8 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and2-chloro-5-(3,4-dimethoxylphenyl)pyrimidine (1.60 g, 6.4 mmol) in DMF(50 mL, anhydrous) were reacted to yield the product as a white solid.

[0226] mp: 173-175° C.; MS (m/z): 507 (MH⁺)

[0227]¹H-NMR (CDCl₃) δ2.89 (d, J=15 Hz, 1 H), 3.02 (m, 1 H), 3.39 (m, 1H), 3.92, 3.94 (2s, 6 H), 5.03 (d, J=12 Hz, 1 H), 5.92 (d, J=4 Hz, 2 H),6.71 (d, J=7 Hz, 1 H), 6.87-7.32 (m, 6 H), 7.56 (d, J=7 Hz, 2 H), 7.80(s, 1H), 8.5 (s, 2H);

EXAMPLE 141-(3,4-Methylenedioxyphenyl)-2-[5-(4-methylphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0228] Following the same procedure as outlined in Example 12,1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.19 g,7.5 mmol) (prepared according to the process as disclosed in WO97/43287,Intermediate 7, page 24) and 2-chloro-5-(4-methylphenyl)pyrimidine (1.03g, 5 mmol) in toluene (50 mL, anhydrous) and DBU (0.9 mL) were reactedto yield the product as a white solid.

[0229] MS (m/z): 459 (MH⁺)

[0230]¹H-NMR (CDCl₃) δ2.43 (s, 3 H), 2.85 (d, J=14 Hz, 1 H), 3.01 (t,J=12 Hz, 1 H), 3.38 (t, J=12 Hz, 1 H), 5.04 (dd, J=14 Hz, 1 H), 5.88 (d,J=4 Hz, 2 H), 6.73 (d, J=7 Hz, 1 H), 6.89 (d, J=7 Hz, 1 H), 7.02 (s, 1H), 7.25-7.50 (m, 7 H), 7.56 (d, J=7 Hz, 1 H), 7.79 (s, 1H), 8.54 (s,2H);

EXAMPLE 151-(3,4-Methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carboline

[0231] A solution of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.92 g,10 mmol) (prepared according to the process as disclosed in WO97/43287,Intermediate 7, page 24), 4-picolylchloride hydrochloride (1.64 g, 10mmol) and DBU (3.1 g, 20 mmol) in DMF (50 mL) was stirred at roomtemperature for 16 h. Water (100 mL) and ethyl acetate (100 mL) wereadded to the reaction mixture. The solute, present in the organic phase,was purified by column chromatography (silica gel, ethyl acetate) toyield the product as an off-white solid.

[0232] MS (m/z) 382 (M−1)

[0233]¹H NMR (CDCl₃) δ2.65 (m, 1 H), 2.75 (d, 1 H), 2.88 (m, 1 H), 3.15(m, 1 H), 3.35 (d, J=15 Hz, 1 H), 3.92 (d, J=15 Hz, 1 H), 4.57 (s, 1 H),5.94 (s, 1 H), 6.79 (d, J=8 Hz, 1 H), 6.89 (m, 2 H), 7.20-7.40 (m, 7 H),7.51 (d, J=6 Hz, 1 H), 8.53 (d, J=7 Hz, 1 H);

EXAMPLE 161-(3,4-Methylenedioxyphenyl)-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0234] 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline(2.3 g, 8.0 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and 2-chloropyrimidine (0.914 g,8.0 mmol) were stirred in anhydrous DMF (15 mL) at 140° C. for 24 h. Thereaction mixture was diluted with ethyl acetate (100 mL) and washed withsaturated aqueous NH₄Cl solution (100 mL). The aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (2×80 mL) and dried with MgSO₄. The solvents wereevaporated and the product was isolated by column chromatography (silicagel, EtOAc:Hexane=1:9 ) as a yellowish solid.

[0235] mp: 176-177° C.;

[0236] MS (m/z): 371 (MH⁺), 369 (M−1); Anal. calculated for C₂₂H₁₈N₄O₂,C 71.34, H 4.90, N 15.13; found C, 70.57, H, 4.92, N 15.38

[0237]¹H NMR (CDCl₃) δ2.71 (m, 1H), 2.92 (m, 1H), 3.29 (m, 1H), 4.92(dd, 1H, J=14, 7 Hz), 5.91 (d, 2H, J=6 Hz), 6.43 (t, 1H, J=6Hz), 6.63(d, 1H, J=10 Hz), 6.81 (d, 1H, J=10 Hz), 6.95 (s, 1H), 7.08 (m, 3H),7.21 (d, 1H, J=8 Hz), 7.54 (d, 1 H, J=10 Hz), 8.12 (s, 1H), 8.30 (d, 2H,J=6 Hz);.

EXAMPLE171-(3,4-Methylenedioxyphenyl)-2-[5-(4-chlorophenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0238] Following the same procedure as outlined in Example 12 above,1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (295 mg,1 mmol) (prepared according to the process as disclosed in WO97/43287,Intermediate 7, page 24) and 2-chloro-5-(4-chlorophenyl)pyrimidine (113mg, 0.5 mmol) in DMF (5 mL, anhydrous) were reacted to yield the productas a white solid.

[0239] MS (m/z): 479 (MH⁺)

[0240]¹H-NMR (CDCl₃) δ2.87 (dd, J=4, 14 Hz, 1 H), 3.01 (dt, J=5, 12 Hz,1 H), 3.38 (dt, J=4, 14Hz, 1 H), 5.04 (dd, J=5, 14Hz, 1 H), 5.91 (d,J=4Hz, 2 H), 6.73 (d, J=7 Hz, 1 H), 6.89 (d, J=7 Hz, 1 H), 7.00 (s, 1H), 7.20 (s, 1 H), 7.25 (m, 2 H), 7.30 (d, J=7 Hz, 1 H), 7.40 (m, 4 H),7.56 (d, J=7 Hz, 1 H), 7.83 (s, 1H), 8.54 (s, 2H);

EXAMPLE 18[5-(3,4-Dimethoxyphenyl)-pyrimidin-2-yl]-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0241] Following the same procedure as outlined in Example 16,1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (preparedaccording to the process as disclosed in WO97/43287, Intermediate 7,page 24) and 2-chloro-5-(3,5-dimethoxyphenyl)pyrimidine were reacted toyield the product as a white solid.

[0242] mp. 184-186° C.;

[0243] MS (m/z) 523 (MH⁺), 521 (M−1)

[0244]¹H NMR (CDCl₃) β2.81˜3.20 (m, 2H), 3.40 (m, 1H), 3.71 (s, 3H),3.79 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 5.01 (dd, 1H, J=14 Hz, 5 Hz),6.68 (d, 1H, J=8 Hz), 6.70˜7.19 (m, 7H), 7.28 (t, 1H, J=8 Hz), 7.52 (t,1H, J=8 Hz), 8.20 (s, 1H), 8.52 (s, 2H);

EXAMPLE 191,2,3,4-Tetrahydro-3-(3,4-dimethoxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#12)

[0245] 1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (1.854g, 6.04 mmol) (prepared as in Example 11) and KOt-Bu (1.14 g, 10.15mmol) were stirred in DMF (60 mL) at room temperature for 10 min. Oxygenwas bubbled through the solution for 1 h. The reaction mixture wasneutralized with 1N HCl solution (10.15 mL, 10.15 mmol) and the waterremoved in vacuo as an azeotrope with toluene. Silica gel (˜5 g) wasadded to the residual DMF solution, followed by diethyl ether (600 mL),which resulted in precipitation of the product onto the silica gel. Thediethyl ether was decanted and the silica gel was washed with diethylether (2×100 mL). After the solvent was decanted and any remaining traceamounts evaporated, the residue was purified by column chromatograph(silica gel; EtOH:EtOAc=1:9) to yield the product as a bright yellowsolid. The product was recrystallized from methanol.

[0246] mp. 223-225 ° C.;

[0247] MS (m/z): 323 (MH⁺), 321 (M−1)

[0248]¹H NMR (CD₃OD) β3.71 (s, 3H), 3.88 (s, 3H), 4.18 (d, 1H, J=14 Hz),4.38 (d, 1H, J=14 Hz), 5.41 (s, 1H), 6.83 (m, 3H), 7.39 (t, 1H, J=7 Hz),7.58 (m, 2H), 8.22 (d, 1H, J=6 Hz), 11.85 (s, 1H);

EXAMPLE 201,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#2)

[0249] Sodium hydride (60% in mineral oil, 36 mg, 0.9 mmol) and1-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline(186 mg, 0.39 mmol) (prepared as in Example 12) in DMF (10 mL,anhydrous) were stirred at room temperature for 30 min. Dry air was thenbubbled through the solution for 16 h. Ethyl acetate (100 mL) andsaturated NaHCO₃ were added, the organic phase was washed with water,brine, and dried with MgSO₄. Solvent was evaporated and the residuetriturated with ethyl acetate to yield the product as a white solid.

[0250] mp: 325-327° C.;

[0251] MS (m/z) 491 (MH⁺); 489 (M−1)

[0252]¹H NMR (DMSO-d₆) δ3.77 (s, 3 H), 4.86 (d, J=12 Hz, 1 H), 4.96 (dd,J=15Hz, 1 H), 5.98 (s, 2 H), 6.29 (d, J=2.5 Hz, 1 H), 6.87 (d, J=8 Hz, 1H), 6.95 (d, J=9 Hz, 2 H), 6.98 (s, 1 H), 7.02 (d, J=4 Hz, 3 H), 7.34(t, J=7 Hz, 1 H), 7.57 (d, J=9 Hz, 2 H), 7.63 (dd, J=8 Hz, 3 H), 8.16(d, J=8 Hz 1 H), 8.69 (broad, s, 2 H); 11.85 (s, 1 H);

EXAMPLE 211,2,3,4-Tetrahydro-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#1)

[0253] Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline(218 mg, 0.43 mmol) (prepared as in Example 13) in DMF (10 mL,anhydrous) were stirred at room temperature for 30 min. Dry air was thenbubbled through the solution for 16 h. Ethyl acetate (100 mL) andsaturated NaHCO₃ were added, the organic phase was washed with water,brine, and dried with MgSO₄. Solvent was evaporated and the residuepurified by chromatography (silica gel, ethyl acetate) to yield theproduct as a white solid.

[0254] MS (m/z) 521 (MH⁺); 519 (M−1)

[0255]¹H NMR (DMSO-d₆) δ3.77 (s, 3 H), 3.83 (s, 3 H), 4.86 (d, J=12 Hz,1 H), 4.96 (dd, J=15 Hz, 1 H ), 5.99 (s, 2 H), 6.31 (d, J=2.5 Hz, 1 H),6.87 (d, J=8 Hz, 1 H), 6.95 (d, J=9 Hz, 2 H), 6.98 (s, 1 H), 7.02 (m, 1H), 7.17 (d, J=7 Hz, 1 H), 7.22 (s, 1 H), 7.35 (t, J=7 Hz, 1 H), 7.62(m, 2 H), 8.17 (d, J=8 Hz, 1 H), 8.74 (broad, s, 2 H); 11.85 (s, 1 H);

EXAMPLE 21A(S)-1,2,3,4-Tetrahydro-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#35)

[0256] Following the procedure as described in Example 21,(S)-1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolinewas reacted to yield the title compound.

EXAMPLE 21B(R)-1,2,3,4-Tetrahydro-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#36)

[0257] Following the procedure as described in Example 21,(R)-1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolinewas reacted to yield the title compound.

EXAMPLE 221,2,3,4-Tetrahydro-2-[5-(4-methylphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#7)

[0258] Following the same procedure as outlined in Example 21, sodiumhydride (60% in mineral oil, 43 mg, 1.09 mmol) and1-(3,4-methylenedioxyphenyl)-2-[5-(4-methylphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline(278 mg, 0.60 mmol) (prepared as in Example 12) in DMF (15 mL,anhydrous) were reacted to yield the product as a white solid.

[0259] MS (m/z) 475 (MH⁺)

[0260]¹H NMR (DMSO-d₆) δ2.32 (s, 3 H), 4.86 (d, J=12 Hz, 1 H), 4.96 (dd,J=15Hz, 1 H), 5.98(s, 2 H), 6.30 (d, J=2.5 Hz, 1 H), 6.87 (d, J=8 Hz, 1H), 6.95 (d, J=9 Hz, 2 H), 7.02 (d, J=4 Hz, 3 H), 7.24 (d, J=7 Hz, 2 H),7.34 (t, J=7 Hz, 1 H), 7.40-7.65 (m, 3 H), 8.16 (d, J=8 Hz, 1 H), 8.69(broad, s, 2 H); 11.85 (s, 1 H);

EXAMPLE 231,2,3,4-Tetrahydro-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-dimethoxyphenyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#15)

[0261] Following the same procedure as outlined in Example 19,[5-(3,4-Dimethoxyphenyl)-pyrimidin-2-yl]-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline(prepared as in Example 18) was reacted to yield the product as a whitesolid.

[0262] MS (m/z) 535 (MH⁺), 537 (MH⁻)

[0263]¹H NMR (CD₃OD) δ3.74 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.85 (s,3H), 5.0 (m, 2H), 6.31 (s, 1H), 6.75˜7.15 (m, 5H), 7.36 (t, 1H, J=8 Hz),7.32 (d, 1H, J=8 Hz), 7.61 (m, 2H), 8.29 (d, 1 H, J=8 Hz), 8.58 (s, 2H);

EXAMPLE 241,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-9H-pyrrolo-[3,4-b]quinolin-9-one(#5)

[0264] Following the same procedure as outlined in Example 21, sodiumhydride (60% in mineral oil, 40 mg, 1.0 mmol) and1-(3,4-methylenedioxyphenyl)-2-(pyridin4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carboline(192 mg, 0.50 mmol) (prepared as in Example 15) in DMF (10 mL,anhydrous) were reacted to yield the product as a white solid.

[0265] MS (m/z) 398 (MH⁺)

[0266]¹H NMR (DMSO-d₆) δ3.58 (d, J=14 Hz, 1 H), 3.76 (d, J=15 Hz, 1 H),3.88 (d, J=15 Hz, 1 H), 4.01 (d, J=14 Hz, 1 H), 5.17 (s, 1 H), 6.03 (s,1 H), 6.97 (s, 3 H), 7.7.35 (m, 3 H), 7.60 (m, 2 H), 7.34 (t, J=7 Hz, 1H), 8.11 (d, J=8 Hz, 1 H), 8.53 (d, J=6 Hz 2 H); 11.45 (s, 1 H);

EXAMPLE 251,2,3,4-Tetrahydro-2-(tert-butoxycarbonyl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#3)

[0267]2-t-Butoxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline(4.09 g, 10.4 mmol) (prepared as in Example 9) was dissolved in dry DMF(100 mL). Potassium t-butoxide (2.55 g, 22.7 mmol) was introduced in oneportion and the suspension was stirred until a clear solution wasobtained. Oxygen gas was then passed through the solution via a syringeneedle for 16 h. The reaction was quenched by the addition of glacialacetic acid (25 mmol) and poured into a mixture of diethyl ether andwater, which resulted in a precipitate that was collected by filtration.The product was purified by flash chromatography (0-10% MeOH/CHCl₃) toyield the product as a white solid.

[0268] MS (m/z): 405 (M−1)

[0269]¹H-NMR (CDCl₃) δ1.38-1.65 (series of s, 9 H), 4.79-4.88 (m, 2 H),5.86-6.27 (series of m, 3 H), 6.71-7.50 (series of m, 7 H), 11.57 and11.64 (s, 1 H);

EXAMPLE 261,2,3,4-Tetrahydro-2-(benzyloxycarbonyl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#27)

[0270]2-benzyloxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline(3.63 g, 8.51 mmol) ) (prepared as in Example 10) was dissolved in dryDMF (25 mL). Potassium t-butoxide (2.40 g, 21.4 mmol) was introduced inone portion and the suspension was stirred until a clear solution wasobtained. Oxygen gas was then passed through the solution via a syringeneedle for 16 h. The reaction was quenched by the addition of glacialacetic acid (1.23 mL, 21.0 mmol) and poured into water (250 mL), whichresulted in a precipitate that was collected by filtration. The productwas purified by flash chromatography (2-10% MeOH/CHCl₃) to yield theproduct as a red powder.

[0271] MS (m/z): 439 (M−1)

[0272]¹H-NMR (CDCl₃) δ4.63-5.18 (series of m, 4 H), 5.71-5.85 (series ofm, 3 H), 6.54-6.72 (series of m, 3 H), 6.98-7.01 (m, 1 H), 7.25-7.57(series of m, 7 H), 8.27-8.32 (m, 1 H), 10.04 and 10.33 (s, 1 H);

EXAMPLE 27(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid, methyl ester (#20)

[0273] A. A solution of (E)-4-carbomethoxycinnamic acid (5.09 g, 24.7mmol) was dissolved in dry THF (25 mL) and treated under an argonatmosphere with oxalyl chloride (3.00 mL, 34.4 mmol) and a drop of dryDMF. After heating at 50° C. for 2 hours, the reaction mixture wasconcentrated in vacuo to yield the acid chloride of (E)-carboxymethylcinnamic acid as a tan solid.

[0274] B. The product from Part A (78 mg, 0.35 mmol) was added to asolution of1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one(93.5 mg, 0.31 mmol) (prepared as in Example 6), THF (3 mL),triethylamine (0.20 mL, 1.43 mmol), and DMAP (5 mg). The mixture wasstirred for 16 h at room temperature, diluted with 1N HCl (10 mL) andthe resulting white precipitate collected by filtration. The solid waswashed with water (3×), with diethyl ether (3×) and dried in vacuo toyield the product as a slightly pink solid.

[0275] MS (m/z): 493 (MH⁺)

[0276]¹H-NMR (DMSO) δ3.10-3. m, 2H), 3.87 (s, 3 H), 4.43-4.52 (m, 2 H),4.70-5.14 (series of m, 2 H), 6.23 and 6.61 (s, 1 H), 6.72-6.79 (m, 1H), 7.07-8.19 (series of m, 12 H), 10.69 and 10.77 (s, 1 H).

EXAMPLE 28 2,3,4-Tetrahydro-3-(34-methylenedioxyphenyl)-2-[5-(3-trifluoromethylphenyl)furoyl]-9H-pyrrolo-[3,4-b]quinolin-9-one(#13)

[0277] To a solution of 5-(3-trifluoromethylphenyl)-2-furoic acid (80.44mg, 0.314 mmol) in 1:1 DCM:THF (5 mL, anhydrous) was added oxalylchloride (43.85 mg, 0.345 mmol), followed by two drops of DMF. Themixture was stirred at room temperature for 1 h. A suspension of1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(96.2 mg, 0.314 mmol) (prepared as in Example 5), triethylamine (0.13mL), and DMAP (trace) in 1:1 DCM:THF (5 mL) was added. The resultingmixture was stirred at room temperature for 16 h. Ethyl acetate (50 mL)was added, and the solution was washed with aq. NaHCO₃, brine, 1N HCl,brine and then dried with MgSO₄. The solvent was evaporated and theresidue triturated with ethyl acetate to yield the product as a whitesolid.

[0278] mp: 219-221° C.

[0279] MS (m/z): 545 (MH⁺), 567 (M+23), 543 (MH⁻)

[0280]¹H-NMR (DMSO-d₆) δ5.09 (d, J=14 Hz, 1 H), 5.46 (d, J=14 Hz, 1 H),5.99 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J=8 Hz, 1 H), 6.97 (d, J=9 Hz, 1H), 7.02 (s, 1 H), 7.33 (d, J=8 Hz, 1 H), 7.38 (d, J=4 Hz, 1 H), 7.43(d, J=4 Hz, 1 H), 7.60 (m, J=8 Hz, 2 H), 7.77 (d, J=5 Hz, 2 H), 8.16 (d,J=4 Hz, 3 H), 11.55 (s, 1 H).

EXAMPLE 291,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(6-hydroxy-2-benzo-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#9)

[0281] To a solution of 6-hydroxy-2-benzofuranoic acid (0.054 g, 0.3mmol) in tetrahydrofuran (5 mL) at 0° C. was added dropwise oxalylchloride (0.046 g, 0.36 mmol) followed by DMF (2 drops). The solutionwas warmed to 25° C. and stirred for 30 min, then concentrated in vacuo.The residue was dissolved in tetrahydrofuran (5 mL), and added to asolution of1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(0.092 g, 0.3 mmol) (prepared as in Example 5) in THF (5 ml),triethylamine (0.045 g, 0.45 mmol) and 4-dimethylaminopyridine (0.01 g,cat.). The solution was stirred for 20 h at 25° C., and thenconcentrated in vacuo. The resulting crude residue was purified bysilica gel column chromatography, eluting with 3% methanol indichloromethane, to yield the product as a clear oil.

[0282]¹H NMR (CD₃OD): δ5.25 (d, J=15 Hz, 1H), 5.48 (d, J=15 Hz, 1H),5.91 (s, 2H), 6.45 (broad s, 1H), 6.84 (m, 3H), 6.93 (m, 2H), 7.00 (s,1H), 7.25-7.89 (overlapping m's, 5H), 8.32 (d, 1H).

EXAMPLE 30(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid methyl ester (#6)

[0283] Following the procedure outlined in Example 20,1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(398 mg, 1.30 mmol) (prepared as in Example 5) was reacted with the acidchloride of (E)-carboxymethyl cinnamic acid (301 mg, 1.34 mmol), in thepresence of triethylamine (0.54 mL, 3.87 mmol) in a 1:1 mixture ofdichloromethane:THF (40 mL) to yield the product as a tan solid.

[0284] MS (m/z): 493 (M−1)

[0285]¹H-NMR (CD₃OD) δ3.86 (s, 3 H), 4.69-5.29 (series of m, 2 H),5.93-6.02 (m, 2 H), 6.27 and 6.62 (s, 1 H), 6.89-8.21 (series of m, 13H), 9.50 and 11.96 (broad s, 1 H).

EXAMPLE 311,2,3,4-Tetrahydro-2-(imidazol-1-yl)thiocarbonyl-3-(3,4-methylenedioxy-phenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#18)

[0286] To a suspension of 1,1′-thiocarbonyldiimidazole (0.192 g, 1.08mmol) in DMF (5 mL, anhydrous) at 0° C. was added1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(0.30 g, 0.98 mmol) (prepared as in Example 5). The mixture warmed toroom temperature and stirred for 20 h. The solution was diluted withwater and extracted into ethyl acetate. The organic layers were combinedand washed with aq. NaHCO₃ and brine, dried with MgSO₄ and concentratedin vacuo, to yield the product as a light tan solid.

[0287] mp: 211-215° C. (dec.)

[0288] MS (m/z): 415 (M−1)

[0289]¹H-NMR (CD₃OD) δ4.71-5.16 (m, 1 H), 5.46 (d, J=15Hz, 1 H),6.36-7.17 (overlapping m's, 5 H), 7.42 (m, 2 H), 7.52 (m, 1 H), 7.58 (m,2 H), 8.28 (m, 1 H).

EXAMPLE 32(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid (#8)

[0290](E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid methyl ester (149 mg, 0.30 mmol), (prepared as in Example 30) wassuspended in a 1:1 mixture of 1 N aqueous sodium hydroxide:methanol (10mL) and heated to reflux for 8 h. The reaction mixture was treated withaqueous HCl to pH 1, resulting in a white precipitate. The precipitatewas collected by filtration and washed with water (30 mL) and diethylether (160 mL) to yield the product as a white solid.

[0291] MS (m/z): 481 (MH⁺)

[0292]¹H-NMR (DMSO) δ4.71-5.13 (series of d, 2 H,), 5.95-5.98 (m, 2 H),6.23 and 6.61 (s, 1 H), 6.84-7.78 (series of m, 10 H), 7.89-7.92 (m, 3H), 8.13-8.17 (m, 1 H), 11.94 (broad s, 1 H).

EXAMPLE 331,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-nitrophenyl)-furoyl]-9H-pyrrolo[3,4-b]quinolin-9-one(#16)

[0293]1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(70.3 mg, 0.229 mmol) (prepared as in Example 5),5-(4-nitrophenyl)-2-furoic acid (58.9 mg, 0.25 mmol) and PyBrOP (0.118g, 0.25 mmol) were stirred in DMF (3 mL) and DIPEA (0.088 mL, 0.50 mmol)for 16 h. The reaction mixture was poured into ethyl acetate (80 mL) andthe resulting organic layer washed with 1N aqueous HCl (3×50 mL),saturated aqueous Na₂CO₃ solution (1×50 mL) and brine (1×50 mL). Theorganic layer was dried with MgSO₄ and the solvent evaporated in vacuo.Column chromatography of the residue (silica gel, 5% CH₃OH/CH₃Cl)yielded the product as a yellow powder.

[0294] MS (m/z): 522 (MH⁺), 520 (M−1)

[0295]¹H NMR (DMSO-d₆) β5.05 (d, 1H, J=14 Hz), 5.45 (d, 1H, J=14 Hz),6.0 (s, 2H), 6.42 (s, 1 H), 6.95 (m, 3H), 7.32˜7.41 (m, 2H), 7.55˜7.65(m, 3H), 8.12 (m, 3H), 8.39 (m, 2H), 11. 91 (s, 1H).

EXAMPLE 341,2,3,4-tetrahydro-3(3,4-methylenedioxyphenyl)2-[5-(4-aminophenyl)-furoyl]-9H-pyrrolo[3,4-b]quinolin-9-one(#26)

[0296]1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[(5-(4-nitrophenyl))-furoyl]-9H-pyrrolo[3,4-b]quinolin-9-one(25 mg, 0.0479 mmol) (prepared as in Example 33) was stirred with 10% Pdon Carbon (5.1 mg, 0.00479 mmol) under 1 atm H₂ at room temperature for14 h. The solvent was evaporated and product isolated by preparative TLCas a yellow powder.

[0297] MS (m/z): 492 (MH⁺); 490 (M−1)

[0298]¹H NMR (CD₃OD) δ5.25 (d, 1H, J=14 Hz), 5.45 (d, 1H, J=14 Hz), 5.91(s, 2H), 6.45 (s, 1H), 6.70˜8.60 (m, 13 H).

EXAMPLE 351,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[2-hydroxynicotinoyl)-9H-pyrrolo[3,4-b]-quinolin-9-one(#25)

[0299] Following the procedure outlined in Example 33, with appropriatesubstitution of reagents, the product was obtained as a pale yellowsolid.

[0300] MS (m/z): 428 (MH⁺); 426 (M−1)

[0301]¹H NMR (CD₃OD) δ4.65 (d, J=14 Hz), 5.10 (d, 1H, J=14 Hz), 5.85 (s,2H), 5.92 (s, 1H), 6.50˜7.10 (m, 3H), 7.30˜7.70 (m, 5H), 8.25 (m, 2H).

EXAMPLE 361,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)-furoyl]-9H-pyrrolo[3,4-b]-quinolin-9-one(#21)

[0302] Following the procedure outlined in Example 33, with appropriatesubstitution of reagents, the product was obtained as a pale yellowsolid.

[0303] MS (m/z): 507 (MH⁺); 505 (M−1)

[0304]¹H NMR (CDCl₃) δ3.85 (s, 3H), 5.10 (d, 1H, J=14 Hz), 5.38 (d, 1H,J=14 Hz), 6.02 (s, 2H), 6.41 (s, 1H), 6.80˜8.35 (m, 13H), 11.80 (s, 1H).

EXAMPLE 371,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-hydroxyphenyl)-furoyl]-9H-pyrrolo[3,4-b]-quinolin-9-one(#22)

[0305] Following the procedure outlined in Example 33, with appropriatesubstitution of reagents, the product was obtained as a pale yellowsolid.

[0306] MS (m/z): 493 (MH⁺); 491 (M−1)

[0307]¹H NMR (DMSO-d₆) δ5.05 (d, 1H, J=14 Hz), 5.15 (d, 1H, J=14 Hz),5.75 (s, 2H), 6.31 (s, 1H), 6.80˜8.35 (m, 13H), 11.60 (s, 1H).

EXAMPLE 381,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxycarbonylphenyl)-furoyl]-9H-pyrrolo[3,4-b]-quinolin-9-one(#24)

[0308] Following the procedure outlined in Example 33, with appropriatesubstitution of reagents, the product was obtained as a pale yellowsolid.

[0309]¹H NMR (DMSO-d₆) δ4.10 (s, 3H), 5.10 (d, 1H, J=14 Hz), 5.50 (d,1H, J=14 Hz), 6.02 (s, 2H), 6.45 (s, 1H), 6.80˜8.35 (m, 13H);

EXAMPLE 391,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-formylphenyl)-furoyl]-9H-pyrrolo[3,4-b]-quinolin-9-one(#23)

[0310] Following the procedure outlined in Example 33, with appropriatesubstitution of reagents, the product was obtained as a pale yellowsolid.

[0311] MS (m/z): 503 (M−1)

[0312]¹H NMR (DMSO-d₆) δ5.10 (d, 1H, J=14 Hz), 5.55 (d, 1H, J=14 Hz),6.02 (s, 2H), 6.45 (s, 1H), 6.80˜8.35 (m, 13H).

EXAMPLE 40(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)4-methyl-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid, methyl ester (#63) &(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9-methoxy-9H-pyrrolo-[3,4-b]quinolin-2-yl]-1-propenyl]benzoicacid, methyl ester (#64)

[0313] A solution of(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid methyl ester (349 mg, 0.62 mmol) (prepared as in Example 30) andiodomethane (0.060 mL, 0.96 mmol) in dry acetone (10 mL) was treatedwith anhydrous potassium carbonate (241 mg, 1.74 mmol) and heated toreflux for 3 h under an argon atmosphere. The reaction mixture wasconcentrated in vacuo and the residue purified by flash chromatography(0-10% methanol in dichloromethane) to yield a mixture of the N- andO-methylated products.

[0314] The mixture of N- and O-methylated products was separated bycolumn chromatography (0-10% MeOH/DCM) to yield the N-methylated product(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-4-methyl-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoicacid, methyl ester as a tan solid.

[0315] MS (m/z): 509 (M−1)

[0316]¹H-NMR (CDCl₃) δ3.55 (s, 3 H), 3.93 (s, 3 H), 5.10 (m, 2 H), 5.94(nd, J=3.7 Hz, 2 H), 6.53 (s, 1 H), 6.78 (d, J=7.9 Hz, 1 H), 6.86-6.96(m, 3 H), 7.44-7.76 (series of m, 6 H), 8.05 (d, J=8.2 Hz, 2 H), 8.55(d, J=7.4 Hz).

[0317] and the O-methylated product(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9-methoxy-9H-pyrrolo-[3,4-b]quinolin-2-yl]-1-propenyl]benzoicacid, methyl ester as a pink solid.

[0318] MS (m/z): 509 (M−1)

[0319]¹H-NMR (CDCl₃) δ3.93 (s, 3 H), 4.38 (s, 3 H), 5.45 (d, J=17.1 Hz,1 H), 5.64 (d, J=17.1 Hz, 1 H), 5.91 (s, 2 H), 6.26 (s, 1 H), 6.75-7.09(series of d, 4 H), 7.39-8.23 (series of m, 9 H).

EXAMPLE 411,2,3,4-Tetrahydro-2-(pyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#11)

[0320] To a solution of1-(3,4-methylenedioxyphenyl)-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline(0.153 g, 0.415 mmol) (prepared as in Example 16) in anhydrous DMF (4.1mL) was added KOtBu (0.079 g, 0.70 mmol, 1.7 eq.). After 5 min, oxygengas was bubbled through the solution for 1 h. Diethyl ether (45 mL) wasadded to the reaction mixture and the supernatant decanted. Brine (2 mL)was added to the residue and the pH was adjusted to pH˜7 by addition ofa few drops of 1N HCl. The water was removed in vacuo as an azeotropewith toluene. The resulting deep red residue was dissolved in a minimumamount of THF, and purified by column chromatography (silca gel;EtOH:CH₂Cl₂=1:9) to yield the product as a white solid.

[0321] MS (m/z): 383 (M−1); 385 (MH⁺)

[0322]¹H NMR (DMSO-d₆) δ4.84 (dd, 2H, J=14 Hz, 10 Hz), 5.98 (s, 2H),6.25 (s, 1H), 6.69 (t, 1H, J=5 Hz), 6.85 (d, 1H, J=8 Hz), 6.92 (d, 1H,J=8 Hz), 7.00 (s, 1H), 7.33 (t, 1H, J=7 Hz), 7.60 (m, 2H), 8.15 (d, 1H,J=8 Hz), 8.41 (broad s, 2H), 11.9 (s, 1H).

EXAMPLE 421,2,3,4-Tetrahydro-2-(pyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#11)

[0323]1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(100 mg, 0.3265 mmol) (prepared as in Example 5) and 2-chloropyrimidine(38 mg, 0.3265 mmol) were stirred in DMF (2.5 mL) at 100° C. for 16 h.The solvent was removed under vacuum and the residue purified by columnchromatography (silica gel, 5% CH₃OH /CH₃Cl) to yield a yellow oil.Trituration of the oil with MeOH afforded the product as a pale yellowsolid.

[0324] MS (m/z): 383 (M−1); 385 (MH⁺)

[0325]¹H NMR (DMSO-d₆) δ4.84 (dd, 2H, J=14 Hz, 10 Hz), 5.98 (s, 2H),6.25 (s, 1H), 6.69 (t, 1H, J=5 Hz), 6.85 (d, 1H, J=8 Hz), 6.92 (d, 1H,J=8 Hz), 7.00 (s, 1H), 7.33 (t, 1H, J=7 Hz), 7.60 (m, 2H), 8.15 (d, 1H,J=8 Hz), 8.41 (broad s, 2H), 11.9 (s, 1H).

EXAMPLE 431,2,3,4-Tetrahydro-2-[(4-pyridinyl)methyloxycarbonyl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (#37)

[0326] A mixture of1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (101 mg, 0.33 mmol) (prepared as in Example 5),(4-pyridinyl)methyl-4-nitrophenylcarbonic acid ester (106 mg, 0.38 mmol)(prepared as in Example 7) and triethylamine (2 eq.) was heated toreflux for 1 h. The reaction mixture was concentrated in vacuo andpurified by flash chromatography (0-10% MeOH/CHCl₃). The correspondingsalt was formed by precipitation of the methanolic solution of the freebase with a solution of HCl-ether.

[0327] MS (m/z) 442 (MH⁺)

[0328]¹H NMR (CD₃OD) δ5.02-5.62 (series of m, 4H), 5.93-6.00 (m, 2H),6.23 and 6.44 (s, 1H), 6.82-7.04 (m, 3H), 7.71-7.90 (m, 4H), 8.12 (d, J6.2 Hz, 1H), 8.44 (s, 1H), 8.78 (s, 1H), 8.84 (s, 1H).

EXAMPLE 441,2,3,4-Tetrahydro-2-[(4-pyridinyl)methyloxycarbonyl]-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#53)

[0329] Following the procedure outlined in Example 36,1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (prepared as in Example 6) and(4-pyridinyl)methyl-4-nitrophenylcarbonic acid ester (prepared as inExample 7) were reacted to yield the product as a slightly pink solid.

[0330] MS (m/z) 440 (MH⁺)

[0331]¹H NMR (DMSO-d6) δ2.82-2.94 (m, 2H), 4.35-5.26 (series of m, 6H),5.91 (s, 1H) 6.45-7.58 (series of m, 9H), 8.30-8.46 (m, 2H), 12.26(broad, 1H).

EXAMPLE 451,2,3,4-Tetrahydro-2-[[5-[2-(4-morpholinyl)ethoxy]-2-benzofuryl]carbonyl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (#49)

[0332]1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (222 mg, 0.65 mmol) (prepared as in Example 5) and6-[2-(1-Morpholino)ethoxy]-2-benzofurancarboxylic acid (209 mg, 0.72mmol) (prepared as in Example 8) were suspended in dry THF (10 mL). Tothis mixture was added PyBrOP (358 mg, 0.77 mmol) and triethylamine(0.40 mL, 2.87 mmol). The mixture was stirred overnight under an argonatmosphere and concentrated in vacuo. Purification of the residue byflash chromatography (0-10% MeOH/CHCl₃) yielded the free base. Thecorresponding salt was formed by precipitation of the methanolicsolution of the free base with a solution of HCl-ether.

[0333] MS (m/z) 580 (MH⁺)

[0334]¹H NMR (DMSO-d6) δ3.17-3.24 (m, 2H), 3.52-3.61 (m, 4H), 3.80 (t,J=11.7 Hz, 2H), 3.98 (d, J=12.1 Hz, 2H), 4.53 (broad s, 1H), 5.10 (d,J=13.3 Hz, 1H), 5.40 (d, J=13.3 Hz, 1H), 6.00 (s, 2H), 6.42 (s, 1H),6.90-7.08 (series of m, 4H), 7.32-7.66 (series of m, 4H), 7.73 (d, J=8.5Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 10.81 (s, 1H), 12.06 (s, 1H).

EXAMPLE 461-(2,3-dihydrobenzofuranyl)-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0335] 1-(2,3-dihydrobenzo-5-furanyl)-2,3,4,9-tetrahydro-1H-β-carboline(prepared according to the process as disclosed in WO97/43287,Intermediate 10, page 25) (3.35 g, 11.54 mmol),5-(4-methoxyphenyl)-2-chloropyrimidine (2.55 g, 11.54 mmol), andN,N-diisopropylethylamine (3.5 mL) were stirred in DMF (10 mL,anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with10% NaCl and extracted with ethyl acetate. The organic layer was washedwith 10% NaCl, brine, and then dried with MgSO₄. The reaction mixturesolvent was evaporated, the resulting residue triturated with CH₂Cl₂ andfiltered. The filtrate was purified by column chromatography (silicagel, ethyl acetate:hexanes=4:6) to yield the product as a white solid.

[0336] mp: 242-243° C.

[0337] MS (m/z): 475 (MH⁺), 483 (M−1)

[0338]¹H-NMR (DMSO-d₆) δ2.50 (s, 1H), 2.83 (m, 2H), 3.12 (t, J=8.7 Hz, 2H), 3.24 (m, 1 H), 3.78 (s, 3 H), 4.49 (t, J=8.7 Hz, 2 H), 4.90 (d, J=12Hz, 1 H), 6.72 (d, J=8.2 Hz, 1 H), 7.03 (m, 4 H), 7.06 (d, J=7 Hz, 1 H),7.17 (d, J=9.3 Hz, 2 H), 7.30 (d, J=8 Hz, 1 H), 7.46 (d, J=7.6 Hz, 1 H),7.59 (d, J=8.6 Hz, 2 H), 8.73 (s, 2H), 11.00 (s, 1H)

EXAMPLE 471,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#39)

[0339] Sodium hydride (60% in mineral oil, 87 mg, 2.18 mmol) and1-(2,3-dihydro-5-benzfuranyl)-2,3,4,9-tetrahydro-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-1H-β-carboline(450 mg, 0.95 mmol) (prepared as in Example 46) in DMF (30 mL,anhydrous) were stirred at room temperature for 30 min. Dry air was thenbubbled through the solution for 16 h. Ethyl acetate (200 mL) was thenadded to the solution. The resulting mixture was washed with 10% NaClsolution, brine and then dried with MgSO₄. The solvent was evaporatedand the residue triturated with ethyl acetate to yield the product as awhite solid.

[0340] mp: 301-302° C.;

[0341] MS (m/z) 489 (MH⁺); 487 (M−1)

[0342]¹H NMR (DMSO-d₆) δ3.11 (t, J=8.7 Hz, 2 H), 3.77 (s, 3H), 4.47 (t,J=8.7 Hz, 2H), 4.89 (m, 2H), 6.29 (s, 1H), 6.72 (d, J=8.1 Hz, 1H), 6.95(d, J=8.7 Hz, 2H), 7.29 (m, 3H), 7.57 (d, J=8.6 Hz, 2 H), 7.64 (d, J=8.2Hz, 2 H), 8.16 (d, J=8.0 Hz, 1 H), 8.67 (s, 2 H), 11.87 (s, 1 H)

EXAMPLE 47A(R)-1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#66)

[0343](R)-1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one(0.23 g, 0.678 mmol) (prepared as in Example 6A), and5-(4-methoxyphenyl)-2-chloropyrimidine (0.167 g, 0.758 mmol) werestirred with diisopropyl ethyl amine (0.33 mL) and KF (44.8 mg, 0.758mmol) in DMF (5 mL) at 60° C. for 36 h. The reaction mixture was dilutedwith CH₂Cl₂ (75 mL) and EtOAc (75 mL). This was washed with 1N aqueousHCl (3×100 mL). This was then washed with brine (2×100 mL). After dryingover MgSO₄, this was concentrated to yellow oil. The crude product waspurified by silica gel column to yield the product as white solid.

[0344] MS (m/z): 499 (MH⁺), 497 (M−1)

[0345]¹H NMR δ CDCl₃ 3.02 (t, 2H, J=11.7 Hz), 3.82 (s, 3H), 4.44 (t, 2H,J=11.7 Hz), 4.95 (d, 1H, J=15.6 Hz), 5.08 (d, 1H, J=15.6 Hz), 6.24 (s,1H), 6.62 (d, 1H, J=7.8 Hz), 6.92 (d, 2H, J=7.8 Hz), 7.14˜7.61 (m, 7H),8.45 (m, 3H), 9.65 (s, 1H)

[0346] Rf=0.47 (10% CH₃OH/CHCl₃). Elemental analysis: for C₃₀H₂₄N₄O₃,calculated %C 73.76, %H 4.95, %N 11.47, %O 9.82; found %C 73.73, %H4.87, %N 11.40, O% 9.65.

EXAMPLE 48(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(3-trifluoromethylphenyl)furo-2-yl]-9H-pyrrolo-[3,4-b]quinolin-9-one(#50)

[0347] To a solution of 5-(3-trifluoromethylphenyl)-2-furoic acid (504.4mg, 1.97 mmol) in 1:1 DCM:THF (10 mL, anhydrous) was added oxalylchloride (275 mg, 2.17 mmol), followed by two drops of DMF. The reactionmixture was stirred at room temperature for 2 h. To the reaction mixturewere added triethylamine (1.1 mL), DMAP (trace), and a suspension ofenantiomerically pure1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(603 mg, 1.97 mmol) (prepared as in Example 5A), in 1:1 DCM:THF (10 mL).The resulting mixture was stirred at room temperature for 16 h. Ethylacetate (100 mL) was added, and the solution was washed with aq. NaHCO₃,brine, 1N HCl, brine and then dried with MgSO₄. The reaction mixturesolvent was evaporated and the residue triturated with ethyl acetate toyield the product as a white solid.

[0348] mp: 219-221° C.

[0349] MS (m/z): 545 (MH⁺), 543 (M−1).

[0350] 1H-NMR (DMSO-d₆) δ5.09 (d, J=13 Hz, 1 H), 5.47 (d, J=13 Hz, 1 H),6.00 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J=8 Hz, 1 H), 6.97 (d, J=8 Hz, 1H), 7.02 (s, 1 H), 7.33 (d, J=7 Hz, 1 H), 7.38 (d, J=4 Hz, 1 H), 7.43(d, J=4 Hz, 1 H), 7.60 (m, J=8 Hz, 2 H), 7.77 (d, J=5 Hz, 2 H), 8.16 (d,J=5 Hz, 3 H), 11.90 (s, 1 H)

EXAMPLE 491-(2,3-Dihydrobenzofuranyl)-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0351] 1-(2,3-dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline(prepared according to the process as disclosed in WO97/43287,Intermediate 10, page 25) (1.35 g, 4.66 mmol),2-chloro-5-(2-pyridinyl)-pyrimidine (893 mg, 4.66 mmol) andN,N-diisopropylethylamine (1.4 mL) were stirred in DMF (10 mL,anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with10% NaCl and extracted with ethyl acetate. The extracted organic layerwas washed with 10% NaCl, brine and then dried with MgSO₄. The reactionmixture solvent was evaporated and the residue purified by columnchromatography (silica gel, ethyl acetate:hexanes=4:6) to yield theproduct as a white solid.

[0352] mp: 170-171° C.

[0353] MS (m/z): 446 (MH⁺), 444 (M−1)

[0354]¹H-NMR (DMSO-d₆) δ2.85 (d, J=5 Hz, 2 H), 3.12 (t, J=8.7 Hz, 2H),3.27 (d, J=12.4 Hz, 1 H), 4.96 (d, J=12.6 Hz, 1 H), 6.72 (d, J=8.2 Hz, 1H), 6.99 (t, J=7.4 Hz, 1 H), 7.07 (t, J=7.1 Hz, 2 H), 7.21 (s, 2H),7.31(d, J=8.2 Hz, 2 H), 7.47 (d J=7.6 Hz, 1H), 7.85 (d, J=7.8 Hz, 1 H),7.93 (d, J=8 Hz, 1 H), 8.62 (d, J=4.5 Hz, 1 H), 9.13 (s, 2H), 11.01 (s,1H)

EXAMPLE 501,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#61)

[0355] Sodium hydride (60% in mineral oil, 182 mg, 4.55 mmol) and1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carboline(16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) in DMF (30mL, anhydrous) were stirred at room temperature for 30 min. Dry air thenwas bubbled through the reaction mixture for 16 h. Ethyl acetate (200mL) was added, and the resulting mixture was washed with 10% NaClsolution, brine, and then dried with MgSO₄. The reaction mixture solventwas evaporated and the residue triturated with ethyl acetate to yieldthe product as a white solid.

[0356] mp: 201-203° C.

[0357] MS (m/z) 460 (MH⁺); 458 (M−1)

[0358]¹H NMR (DMSO-d₆) δ3.11 (t, J=8.5 Hz, 2H), 4.46 (t, J=8.5 Hz, 2H),4.91 (m, 2H), 6.34 (s, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.31 (m, 4H), 7.59(t, J=8.6 Hz, 2 H), 7.84 (d, J=7.1 Hz, 1 H), 7.91 (d, J=7.7 Hz, 1 H),8.16 (d, J=7.9 Hz, 1 H), 8.60 (d, J=4.5 Hz, 1 H), 8.98 (s 1H), 9.12 (s,2 H), 11.90 (s, 1 H).

EXAMPLE 50A(R)-1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#65)

[0359] A. 1-methyl-5-(2-pyridinyl)-2(1H)pyrimidone

[0360] A mixture of 2-(2-pyridinyl)malondialdehyde (5 g, 0.0335 mole),methyl urea (4.72 g, 0.0637 mole), and toluenesulfonic acid (450 mg) wasrefluxed in toluene (100 mL) in an apparatus fitted with a Dean-Starkwater separator for 4 h. The mixture was cooled and the precipitate wasfiltered. The solid was triturated with water and recrystallized fromethanol to yield the product.

[0361] MS m/z (M+H) 188

[0362]¹H NMR (DMSO-d₆) δ7.48 (m, 1H), 7.98 (m, 1H), 8.18(d, J=8.0 Hz,1H), 8.75 (s, 1H), 9.41(s, 2H).

[0363] B. 2-chloro-5-(2-pyridinyl)pyrimidine

[0364] A mixture of 1-methyl-5-(2-pyridinyl)-2(1H)pyrimidone (8.994 g,0.048 mole), phosphorus pentachloride (2.156 g, 0.0104 mole), andphosphorus oxychloride (24 mL) was refluxed at 120° C. for 8 h. POCl₃was distilled out under reduced pressure. The residue was cooled to roomtemperature and ice-water was added. The mixture was extracted withEtOAc, the organic layer was washed with 15% NaCl solution, brine anddried over MgSO₄. Solvent was distilled out under reduced pressure toyield a solid. The water layer was adjusted to pH 6-7 by using saturatedNa₂CO₃, then extracted with EtOAc. The organic layer was washed with 15%NaCl, brine, dried over MgSO₄. Solvent was distilled out under reducedpressure to give a solid. After trituration with MeOH, additionalproduct was obtained.

[0365] MS m/z (M+H) 192

[0366]¹H NMR (DMSO-d₆) δ3.56 (s, 3H), 7.33 (m, 1H), 7.89 (d, J=8.8 Hz,2H), 8.61 (d, J=4.7 Hz, 1H), 8.95 (s, 1H), 9.31 (s, 1H).

[0367] C.(R)-1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one

[0368] A mixture of(R)-1,2,3,4-Tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (1.273 g, 0.00373 mole) (prepared in example 6A),2-chloro-5-(2-pyridinyl)pyrimidine (0.714 g, 0.00373 mole), KF (0.216 g,0.00373 mole), and diisopropylethylamine (2.27 mL) in DMF (45 mL) washeated at 55° C. for 4 h. EtOAc was added, and the mixture was washedwith 0.5N citric acid, then with 15% NaCl, brine and dried over MgSO₄.Solvent was distilled out under reduced pressure to give a solid. Thesolid was dissolved in 10% methanol in dichloromethane and purified viacolumn chromatography (EtOAc to 10% CH₃OH in EtOAc) to yield the titlecompound.

[0369] mp 231-233° C.

[0370] MS m/z (M+H) 460

[0371]¹H NMR (DMSO-d₆) δ3.11 (d, J=8.7 Hz, 2H), 4.46 (d, J=8.7 Hz, 2H),4.92 (m, 2H), 6.34 (d, J=1.6 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.28 (m,4H), 7.59 (m, 2H), 7.82 (m, 1H), 7.91 (d, J=8.0, 1H), 8.16 (d, J=8.0,1H), 8.60, J=4.5 Hz, 1H), 8.98 (s, 1H), 9.12 (s, 1H), 11.92 (s, 1H)

[0372] The title compound was dissolved in methanol, one equivalent of0.02M methane sulfonic acid (in methanol) was added. Solvent wasdistilled out under reduced pressure to yield the methane sulfonic salt.

[0373] [α]=−236.2° (c=1.0333 g/dL, CH₃OH).

EXAMPLE 51 2-chloro-5-bromopyrimidine

[0374] 2-chloro-5-bromopyrimidine was prepared from 2-hydroxypyrimidine(purchased from Frontier Scientific Inc.) according to the proceduredisclosed in U.S. Pat. No. 5,693,611, Preparation 6, Column 17.

EXAMPLE 521-(3,4-Methylenedioxyphenyl)-2-(5-bromopyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0375] To the solution of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (4.38 g,15.0 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and 2-chloro-5-bromopyrimidine(2.90 g, 15.0 mmol) (prepared as in Example 51) in dry degassed DMF (30ml) was added N, N-diisopropylethylamine (4.2 ml, 30 mmol). The mixturewas heated at 120-130° C. overnight. The mixture was then cooled anddiluted with ethyl acetate. The solution was washed with 0.5 N citricacid, water and brine, then dried over Na₂SO₄ and concentrated in vacuo.Purification by flash column (silical gel, hexane:ethyl acetate=6:1,v/v, followed by hexane:ethyl acetate=4:1, v/v ) yielded the product asa white solid.

[0376] MS (m/z) 451 and 449 (MH⁺), 447 and 449 (M−1).

[0377]¹H NMR (CDCl₃) δ2.82-3.02 (m, 2 H), 3.30-3.40 (m. 1 H), 4.92 (dd,J=18.1 Hz, 1 H), 5.92 (d, J=3.2 Hz, 2 H), 6.72 (d, J=8.0 Hz, 1 H), 6.85(d, J=8.0 Hz, 1 H), 6.95 (s, 1 H), 7.02 (s, 1 H), 7.13-7.21 (m, 2 H),7.30 (d, J=7.7 Hz, 1 H), 7.55 (d, J=7.5 Hz, 1 H), 7.73 (s, 1 H), 8.34(s, 2 H).

EXAMPLE 531,2,3,4-Tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#55)

[0378] Method A

[0379] A solution of1-(3,4-methylenedioxyphenyl)-2-(5-bromopyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline(1.0 g, 2.2 mmol) (prepared as in Example 52) in dry DMF (40 ml) wascooled in an ice bath. NaH (60% in mineral oil, 0.18 g, 4.4 mmol) wasadded and the mixture was stirred at 0° C. for 45 min. Dried air wasbubbled through the solution and the mixture was allowed to warm to roomtemperature overnight. The reaction mixture was quenched with water andextracted with ethyl acetate. The organic phase was washed with brineand water, then dried over Na₂SO₄, concentrated and purified by flashcolumn (silica gel, hexane:ethyl acetate=1:1, v/v, followed by neatethyl acetate) to yield the product as a white solid.

[0380] MS (m/z) 465 and 463 (MH⁺), 463 and 461 (M−1).

[0381]¹H NMR (DMSO-d₆) δ4.80 (d, J=8.2 Hz, 1H), 4.89 (dd, J=6.8 Hz, 1H), 5.98 (s, 2H), 6.20 (s, 1H), 6.85-6.93 (m, 2 H), 6.98 (s, 1 H), 7.34(t, J=7.3 Hz, 2 H), 7.57-7.64 (m, 3H), 8.15 (d, J=8.0 Hz, 2 H).

[0382] Method B

[0383] To the solution of1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(31 mg, 0.1 mmol) (prepared as in Example 5, free base) and2-chloro-5-bromopyrimidine (19 mg, 0.1 mmol) (prepared as in Example 51)in dry degassed DMF (2 ml) was added N,N-diisopropylethylamine (28 μl,0.2 mmol). The mixture was heated at 120-130° C. overnight. The solutionwas cooled, diluted with ethyl acetate and washed by 0.5N citric acid,water and brine, then dried over Na₂SO₄ and concentrated in vacuo.Purification by flash column (silica gel, hexane:ethyl acetate=1:1, v/v,followed by neat ethyl acetate) yielded the product as a white solid.

[0384] MS (m/z) 465 and 463 (MH⁺), 463 and 461 (M−1).

[0385]¹H NMR (DMSO-d₆) δ4.80 (d, J=8.2 Hz, 1H), 4.89 (dd, J=6.8 Hz, 1H), 5.98 (s, 2H), 6.20 (s, 1H), 6.85-6.93 (m, 2 H), 6.98 (s, 1 H), 7.34(t, J=7.3 Hz, 2 H), 7.57-7.64 (m, 3H), 8.15 (d, J=8.0 Hz, 2 H).

EXAMPLE 541,2,3,4-Tetrahydro-2-[5-(3-pyridinyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#56)

[0386] Method A

[0387] A stirred mixture of palladium(II) acetate (0.8 mg, 3.6 μmol) and1,1′-bis(diphenylphosphino)ferrocene (dppf) (2.4 mg, 4.3 μmol) in dryDMF (1.0 ml) was warmed to 50° C. for 15 min and then cooled.1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(20 mg, 43 μmol) (prepared as in Example 53), pyridine-3-boronic acid(6.0 mg, 43 μmol) and triethylamine (8 μl, 60 μmol) were added to thesolution and the mixture was heated to 90° C. for 16 h. The solution wasdiluted with ethyl acetate and filtered through filter paper. Theorganic phase was washed with brine and water, and then dried overNa₂SO₄. A small amount of silica gel was added into the solution and thesolution was dried in vacuo. Purification by flash column (silica gel,10% ammonium hydroxide in water:acetonitrile=1:10, v/v) yielded theproduct as a white solid.

[0388] MS (m/z) 460 (M−1).

[0389]¹H NMR (DMSO-d₆) δ4.88 (d, J=4.1 Hz, 1H), 4.99 (d, J=4.1 Hz, 1 H),5.99 (s, 2H), 6.31 (s, 1H), 6.88 (d, J=7.9 Hz, 1 H), 6.96 (d, J=8.1 Hz,1 H), 7.04 (s, 1H), 7.34 (t, J=6.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.56-7.70(m, 2H), 8.08 (d, J=8.0 Hz, 1H), 8.16 (d, J=7.9 Hz, 1 H), 8.53 (d, J=4.1Hz, 1H), 8.72-8.82 (broad, 1H), 8.89 (s, 2H), 11.87 (s, 1H).

[0390] Method B

[0391] A solution of1-(3,4-methylenedioxyphenyl)-2-[5-(3-pyridinyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline(100 mg, 0.22 mmol) (prepared as in Example 55), in dry DMF (4.0 ml) wascooled in an ice bath. NaH (60% in mineral oil, 31 mg, 0.78 mmol) wasadded and the mixture was stirred at 0° C. for 45 min. Dried air wasbubbled through the solution and the mixture was allowed to warm to roomtemperature overnight. The reaction was quenched by water and extractedby ethyl acetate. The organic phase was washed with brine and water,then dried over Na₂SO₄, concentrated and purified by flash column(silica gel, 10% ammonium hydroxide in water:actonitrile=1:10, v/v) toyield the product as a white solid.

[0392] MS (m/z) 460 (M−1).

[0393]¹H NMR (DMSO-d₆) δ4.88 (d, J=4.1 Hz, 1H), 4.99 (d, J=4.1 Hz, 1 H),5.99 (s, 2H), 6.31 (s, 1H), 6.88 (d, J=7.9 Hz, 1 H), 6.96 (d, J=8.1 Hz,1 H), 7.04 (s, 1H), 7.34 (t, J=6.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.56-7.70(m, 2H), 8.08 (d, J=8.0 Hz, 1H), 8.16 (d, J=7.9 Hz, 1 H), 8.53 (d, J=4.1Hz, 1H), 8.72-8.82 (br, 1H), 8.89 (s, 2H), 11.87 (s, 1H).

EXAMPLE 551-(3,4-Methylenedioxyphenyl)-2-[5-(3-pyridinyl)-pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0394] A stirred mixture of palladium(II) acetate (27 mg, 0.12 mmol) and1,1′-bis(diphenylphosphino)ferrocene (dppf) (83 mg, 0.15 mmol) in dryDMF (20 ml) was warmed to 50° C. for 15 min and then cooled.1-(3,4-methylenedioxyphenyl)-2-(5-bromopyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline(674 mg, 1.5 mmol) (prepared as in Example 52), pyridine-3-boronic acid(203 mg, 1.7 mmol) and triethylamine (0.3 ml, 2.1 mmol) were added tothe solution and the mixture heated to 90° C. for 16 h. The solution wasdiluted with ethyl acetate and filtered through filter paper. Theorganic phase was washed with brine and water, then dried over Na₂SO₄. Asmall amount of silica gel was added into the solution and the solutionwas dried in vacuo. Purification by flash column (silica gel,hexane:ethyl acetate=1:1, v/v, followed by hexane:ethyl acetate=1:2,v/v) yielded the product as a white solid.

[0395] MS (m/z) 448 (MH⁺) and 446 (M−1).

[0396]¹H NMR (CDCl₃) δ2.85-3.10 (m, 2H), 3.33-3.48 (m, 1 H), 5.06 (dd,J=8.5 Hz, 1H), 5.94 (d, J=4.7, 2H), 6.73 (d, J=8.0, 1H), 6.90 (d, J=8.0,1H), 7.02 (s, 1 H), 7.13-7.23 (m, 2 H), 7.32-7.42 (m, 2 H), 7.56 (d,J=7.4 Hz, 1H), 7.79-7.84 (m, 2H), 8.58 (s, 1H), 8.60(s, 2H) 8.77 (s,1H).

EXAMPLE 561,2,3,4-Tetrahydro-2-[5-(4-pyridinyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(#57)

[0397] A stirred mixture of1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one(46 mg, 0.1 mmol) (prepared as in Example 53), (PPh₃)₄Pd (3.5 mg, 3.04mol) and 4-tri-n-butylstannylpyridine (37 mg, 0.1 mmol) in dry DMF (2.0ml) was heated at 140° C. for 12 h. More catalyst (3.5 mg) was added andthe mixture was refluxed for 4 h and then cooled. The solution wasdiluted with ethyl acetate and filtered through filter paper. Theorganic phase was washed with brine and water, then dried over Na₂SO₄. Asmall amount of silica gel was added into the solution and dried invacuo. Purification by flash column (silica gel, neat acetonitrilefollowed by 10% ammonium hydroxide in water:actonitrile=1:10, v/v)yielded the product as a white solid.

[0398] MS (m/z) 460 (M−1).

[0399]¹H NMR (DMSO-d₆) δ4.93 (d, J=4.2 Hz, 1H), 5.00 (d, J=4.2 Hz, 1 H),6.01 (s, 2H), 6.33 (s, 1H), 6.90 (d, J=8.0 Hz, 1 H), 6.98 (d, J=8.0 Hz,1 H), 7.05 (s, 1H), 7.34 (broad, 1 H), 7.62 (broad, 2H), 7.77 (d, 2H),8.19 (d, J=7.9 Hz, 1 H), 8.61 (broad, 2H), 8.78 (broad, 1H), 9.00(broad, 1H).

EXAMPLE 571,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(2-bromo)-furoyl)-9H-pyrrolo[3,4-β]quinolin-9-one(#30)

[0400] 5-Bromo-2-furoic acid (1.44 g, 7.54 mmol) in THF (20 mL) wasstirred with oxalyl chloride (1.06 mL, 7.54 mmol) at room temperature.To the mixture was added 2 drops of DMF resulting in a vigorous reactionwith evolution of gas. After the evolution of gas ceased, an additionalquantity of oxalyl chloride (0.1 mL, 0.71 mmol) was introduced viasyringe and the mixture was stirred at room temperature for 10 min andthen stirred at 90° C. for 10 min. Solvent and excess oxalyl chloridewere removed in vacuo, resulting in a pale yellow crystalline solid. Tothe solid was added THF (20 mL) and a solution of3-(2,3-dihydro-5-benzofuran)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one(2.1 g) (prepared as in Example 6), in THF (20 mL). Et₃N (4.55 mL, 32.6mmol) and a catalytic amount of DMAP (40 mg) were then added to thereaction mixture. A few drops of DMF were added, resulting in a clearreaction mixture. The reaction mixture was stirred at room temperaturefor 4 h. The reaction mixture solvent was evaporated resulting in asolid residue. The residue was re-dissolved in CHCl₃ (200 mL), washedwith water (3×200 mL) and the organic layer dried over MgSO₄. Theorganic solvent was evaporated to yield the product as a off-whitesolid.

[0401] MS (m/z): 480, (MH⁺), 478 (M−1)

[0402]¹H NMR CDCl₃ δ5.03 (d, 1H, J=15.5 Hz), 5.23 (d, 1H, J=15.5 Hz),5.85 (d, 2H, J=8.0 Hz), 6.40 (m, 2H), 6.56 (m, 1H), 6.81 (m, 2H), 7.00(d, 1H, J=4.3 Hz), 7.32 (t, 1H, J=8.6 Hz), 7.53 (t, 1H, J=8.6 Hz), 7.65(d, 1H, J=8.6 Hz), 8.38 (d, 1H, J=8.6 Hz), 12.8 (s, 1H).

EXAMPLE 58 4-(4-Methyl)-piperazinylcarbonyl benzeneboronic acid

[0403] 4-Carboxybenzeneboronic acid (0.332 g, 2 mmol),1-methylpiperazine (0.22 mL, 2 mmol) and PyBrOP (0.9334 g, 2 mmol) werestirred with DIPEA (0.696 mL, 4 mmol) in DMF (7 mL) at room temperaturefor 16 h. Preparatory TLC (10% MeOH/CHCl₃) yielded the product as whitesolid.

[0404] MS (m/z): 251 (MH⁺), 249 (M−1)

[0405]¹H NMR CD₃OD δ2.36 (s, 3H), 2.43 (s, 2H), 2.57 (s, 2H), 3.51 (s,2H), 3.82 (s, 2H), 7.34 (s, 2H), 7.76 (s, 2H).

EXAMPLE 591,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)-piperazinylcarbonyl)-phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#44)

[0406]1,2,3,4-Tetrahydro-3-(3,4-methylenedixoyphenyl)-2-(5-(2-bromo-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one(59.6 mg, 0.12 mmol) (prepared as in Example 57), was stirred withPd(PPh₃)₄ (7.37 mg, 0.0062 mmol) in dioxane (5.5 mL) with N₂ bubblingfor 10 min. A solution of 4-(4-methyl)-piperazinylcarbonylbenzeneboronic acid (37.0 mg, 0.15 mmol) and K₂CO₃ (51.5 mg, 0.37 mmol)in H₂O (1.1 mL) was then added. The reaction mixture was stirred at 100°C. for 1 h. The solvent was evaporated, the residue purified bypreparatory TLC (10% MeOH/CHCl₃) and then triturated with ether/MeOH (15mL/1 mL), to yield the product as a pale yellow powder.

[0407] MS (m/z): 603 (MH⁺), 601 (M−1)

[0408]¹H NMR CD₃OD δ2.32 (s, 3H), 2.53-2.62 (m, 4H), 3.53 (broad s, 2H),3.83 (broad s, 2H), 5.17 (d, 1H, J=15.5 Hz), 5.41 (d, 1H, J=15.5 Hz),5.83 (s, 2H), 6.22 (s, 1H), 6.70 (m, 1H), 6.82 (m, 2H), 7.03 (m, 1H),7.25˜7.34 (m, 2H), 7.46˜7.56 (m, 4H), 7.93 (d, 2H, J=8.6 Hz), 8.31 (d,2H, J=8.6 Hz)

EXAMPLE 59A(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)-piperazinylcarbonyl)-phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#69)

[0409] A 5-(4-(4-methyl)-piperazinylcarbonyl phenyl)furoic acid, methylester

[0410] A mixture of 4-(4-methyl)-piperazinylcarbonyl benzeneboronic acid(prepared as in Example 58) (1.31 g, 5.28 mmol), methyl bromofuroicester (1.08 g, 5.28 mmol (prepared from 5-bromofuroic acid in HCl/MeOHfor 5 h at room temperature) was degassed by N₂ bubbling in dioxane (45mL) and H₂O (9 mL) for 10 min. To this was added with Pd(PPh₃)₄ (0.627g, 0.528 mmol) and K₂CO₃ (2.185 g, 15.84 mmol). The solution was stirredat 100° C. for 3 h. Solvent was evaporated and the residue was dissolvedin CH₂Cl₂ (100 mL). This was washed with brine (3×100 mL), dried overMgSO₄, concentration under vacuum and the crude product purified bysilica gel column (5% CH₃OH/CHCl₃) to yield the product as yellow solid.

[0411] MS (m/z): 315 (MH⁺), 313 (M−1)

[0412]¹H NMR δCDCl₃ 2.32˜2.48 (m, 7H), 3.48 (s, 2H), 3.80 (s, 2H), 3.92(s, 3H,), 6.81 (d, 1H, J=2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 7.49 (d, 2H,J=7.9 Hz), 7.83 (d, 2H, J=7.9 Hz)

[0413] Rf=0.51 (10% CH₃OH/CHCl₃).

[0414] B. 5-(4-(4-methyl)-piperazinylcarbonyl phenyl)furoic acid

[0415] To the product from Step A above(5-(4-(4-methyl)-piperazinylcarbonyl phenyl)furoic acid, methyl ester)(1.08 g, 3.29 mmol), dissolved in THF (98.7 mL) was added LiOH (16.45mL, 0.2 N in H₂O). The solution was stirred at room temperature for 3.5h and was neutralized by HCl (3.29 mL, 1.0 M in ether). Afterconcentration, the crude material was used without further purification.

[0416] MS (m/z): 329 (MH⁺), 327 (M−1)

[0417]¹H NMR δ CD₃OD 2.35 (s, 3H), 2.36˜2.58 (br s, 4H,), 3.48 (s, 2H),3.85 (s, 2H), 6.90 (d, J=2.0 Hz), 7.02 (d, 1H, J=2.0 Hz), 7.46 (d, 2H,J=7.9 Hz) 7.95 (d, 2H, J=7.9 Hz)

[0418] C.(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-{5-[4-(1-(4-methyl)-piperazinylcarbonyl)-phenyl]furoyl}-9H-pyrrolo[3,4-b]quinolin-9-one(#69)

[0419] A mixture ofR-1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one,hydrochloride salt (1.12 g, 3.29 mmol) (prepared as in Example 5A), andthe product from Step B (1.034 g, 3.29 mmol) was stirred with PyBroP(1.535 g, 3.29 mmol) and diisopropyl ethyl amine (1.716 mL, 9.87 mmol)in DMF (30 mL) at room temperature for 12 h. The reaction mixture wasdiluted with CH₂Cl₂ (75 mL) and EtOAc (75 mL). This was purified on asilica gel column (neat CH₂Cl₂, to 2.5% CH₃OH/CH₂Cl₂) to yield theproduct as an off-white solid.

[0420] MS (m/z): 603 (MH⁺), 601 (M−1)

[0421]¹H NMR δ CD₃OD δ2.32 (s, 3H), 2.43˜2.55 (m, 4H), 3.53 (br s, 2H),3.83 (br s, 2H), 5.25 (d, 1H, J=15.5 Hz), 5.51 (d, 1H, J=15.5 Hz), 5.87(s, 2H), 6.29 (s, 1H), 6.70 (m, 1H), 6.82 (m, 2H), 7.08 (m, 1H),7.20˜7.39 (m, 2H), 7.46˜7.58 (m, 4H), 8.01 (d, 2H, J=8.6 Hz), 8.31 (d,2H, J=8.6 Hz)

[0422] HPLC Chiralpak OD 4.6×250 mm, 1% DEA/MeOH, Tr=4.846 min)

EXAMPLE 601,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(2-(4-hydroxy)phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one,sodium salt (Na salt of #22)

[0423] Following the procedure outlined in Example 59, with appropriatesubstitution of reagents, the product was obtained as a off-white solid.

[0424] MS (m/z): 493 (MH⁺), 491 (M−1)

[0425]¹H NMR CDCl₃ δ5.21 (d, 1H, J=15.6 Hz), 5.57 (d, 1H, J=15.6 Hz),6.12 (s, 2H), 6.51 (s, 2H) 6.68 (d, 1H, J=4.1 Hz), 6.98˜7.14 (m, 4H),7.38 (s, 1H), 7.48 (t, 1H, J=8.6 Hz), 7.62˜7.79 (m, 4H), 8.08 (s, 1H),8.28 (d, 1H, J=8.6 Hz).

EXAMPLE 61 (4-(2-(1-pyrrolidinyl)ethoxy)phenyl)boronic acid

[0426] (Prepared according to the procedure described by Hoye, T. R. andChen, M. in J. Org. Chem. 1996, 61, 7940.)

[0427] To a solution of 1-[2-(4-bromophenoxy)ethyl]-pyrrolidine (2.70 g,10 mmol) in THF (40 mL) was added n-butyl lithium (6.9 mL 1.6 M inhexanes, 11 mmol) at −78° C. The reaction mixture was stirred at −78° C.for 15 min and then at 0° C. for 15 min. Trimethyl borate (2.5 mL, 22mmol) was then added to the reaction mixture at 0° C. The mixture wasgradually warmed to room temperature overnight. Methyl borate in thereaction mixture was hydrolyzed by reacting with saturated NH₄Cl aqueoussolution (100 mL) at room temperature for 30 min. The upper organiclayer was collected. The aqueous layer was extracted with CHCl₃ (2×100mL). The organic layers were combined, washed with brine (2×100 mL) anddried with MgSO₄. The solvent was evaporated, resulting in a dense oilwhich was purified by column chromatograph (10% MeOH/CHCl₃ and 1% Et₃N)to yield the product as a white solid.

[0428] MS (m/z): 236, (MH⁺), 234 (M−1)

[0429]¹H NMR CD₃OD δ1.81 (m, 4H), 2.67 (m, 4H), 2.89 (t, 2H, J=6.0 Hz),4.08 (t, 2H, J=6.0 Hz), 6.74 (d, 2H, J=8.6 Hz), 7.62 (d, 2H, J=8.6 Hz).

EXAMPLE 621,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(2-(1-pyrrolidinyl)ethoxy)phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#45)

[0430] Following the procedure outlined in Example 59, with appropriatesubstitution of reagents, the product was obtained as a off-white solid.

[0431] MS (m/z): 590, (MH⁺), 588 (M−1)

[0432]¹H NMR CDCl₃ δ2.18 (s, 4H), 2.55 (s, 4H), 2.75 (m, 2H), 2.90 (m,2H), 4.67 (d, 1H, J=15.6 Hz), 4.82 (d, 1H, J=15.6 Hz), 5.18 (s, 2H),5.81 (m, 1H), 6.08 (m, 1H), 6.21 (s, 2H), 6.35 (s, 1H), 6.60 (s, 1H),6.82 (m, 3H), 6.92 (m, 1H), 7.04 (m, 1H), 7.21 (s, 2H), 7.62 (d, 1H,J=8.6 Hz).

EXAMPLE 633-(2,3-Dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-(benzyl)-9H-pyrrolo[3,4-b]quinolin-9-one(#60)

[0433]1-(2,3-Dihydro-5-benzofuranyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline(prepared as in Example 2) (5.25 g, 13.81 mmol), potassium dioxide (3.92g, 55.24 mmol) and 18-crown-6 (3.65 g, 13.81 mmol) were mixed with DMF(100 mL) in a 200 mL flask. The reaction mixture was maintained at roomtemperature overnight. The reaction mixture was slowly added into aseparate 500 mL flask containing a mixture of EtOAc (172 mL), H₂O ( (172mL) and 1N aqueous HCl (50 mL). The mixture was observed to produce tinygas bubbles. The reaction mixture was stirred at 0° C. for 30 min,resulting in the formation of a precipitate at the surface of the twoliquid layers. The precipitate was collected by filtration, washed withH₂O (20 mL) and then dried in a vacuum oven to yield the product as aoff-white solid.

[0434] MS (m/z): 395, (MH⁺), 393 (M−1).

[0435]¹H NMR CDCl3 d 3.12 (t, 2H, J=8.7 Hz), 3.50˜3.65 (m, 2H), 3.99 (d,1H, J=13.0 Hz), 4.22 (d, 1H. J=13.0 Hz), 4.55 (t, 2H, J=8.7 Hz), 4.91(s, 1H), 6.74 (d, 1H, J=8.7 Hz), 7.11˜7.32 (m, 9H), 7.48 (t, 1H, J=8.7Hz 8.30 (t, 1H, J=8.7 Hz)

EXAMPLE 643-(3,4-Methylenedioxyphenyl)-1,2,3,4-tetrahydro-2-[5-(3-trifluoromethyl)phenyl-2-furoyl]-9H-pyrrolo[3,4-b]quinolin-9-one(#13)

[0436] Following the procedure outlined in Example 63, with appropriatesubstitution of reagents,1-(3,4-methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline(0.381 g, 0.719 mmol) was reacted to yield the product as a off-whitesolid. Note that for full formation of the precipitate, the two liquidreaction mixtures were maintained at room temperature for 48 h, ratherthan overnight.

[0437] MS (m/z): 545 (MH⁺), 567 (M+23), 543 (M−1)

[0438]¹H-NMR (DMSO-d₆) δ5.09 (d, J=14 Hz, 1 H), 5.46 (d, J=14 Hz, 1 H),5.99 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J=8 Hz, 1 H), 6.97 (d, J=9 Hz,1H), 7.02 (s, 1 H), 7.33 (d, J=8 Hz, 1 H), 7.38 (d, J=4 Hz, 1 H), 7.43(d, J=4 Hz, 1 H), 7.60 (m, J=8 Hz, 2 H), 7.77 (d, J=5 Hz, 2 H), 8.16 (d,J=4 Hz, 3 H), 11.55 (s, 1 H).

EXAMPLE 651-(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0439] A.1-(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethyloxycarbonyl)thiocarbamoyl]-2,3,4,9-tetrahydro-1H-β-carboline

[0440] A mixture of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.66 g,9.08 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and Fmoc-isothiocyanate (2.82 g,10.14 mmol) was dissolved in dry dichloromethane (50 mL). The mixturewas stirred for 16 hours at ambient temperature, and then concentratedin vacuo. Purification by flash chromatography (0-10% methanol indichloromethane) yielded the protected thiourea as a pale yellow solid.

[0441] MS (m/z): 574 (MH⁺)

[0442]¹H -NMR (CDCl₃) δ2.86 (dd, J=12.9, 5.1 Hz, 1 H), 3.09 (dt, J=17.1,6.9 Hz, 1H), 3.56 (dt, J=12.9, 5.1 Hz, 1 H), 4.19 (t, J=6.9 Hz, 1 H),4.43-4.53 (m, 2 H), 5.91 (s, 2 H), 6.70 (d, J=8 Hz, 1 H), 6.90 (br d,J=7.6 Hz, 1 H), 6.97 (br s, 1 H), 7.11-7.78 (series of m, 17 H)

[0443] B.1-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0444] A solution of the protected thiourea from Part A (4.78 g, 8.33mmol) in 20% (v/v) piperidine in methanol was heated to reflux for 5 h.The mixture was concentrated in vacuo to yield a crude residue which waspurified by flash chromatography (SiO₂, 0-10% methanol indichloromethane) to yield a yellow solid.

[0445] MS (m/z): 352 (MH⁺)

[0446]¹H-NMR (CDCl₃) δ2.69-2.87 (series of m, 2 H), 3.10-3.19 (m, 1 H),4.24 (br s, 1 H), 6.00 (d, J=3.3 Hz, 2 H), 6.72 (d, J=8.0 Hz, 1 H), 6.87(d, J=8.0 Hz, 1 H), 7.00-7.11 (series of m, 3 H), 7.30 (d, J=8.0 Hz,1H), 7.46 (d, J=7.7 Hz, 1H), 7.74 (br s, 3 H), 11.06 (s, 1 H)

[0447] C.1-(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0448] To a solution of the thiourea from Part B (223 mg, 0.63 mmol) ina 1:1 mixture of dioxane:ethanol (5 mL) was added4-methoxyphenyl-2′-bromoacetophenone (175 mg, 0.76 mmol) andtriethylamine (0.40 mL). The mixture was heated to 70° C. for 3 h,cooled to room temperature and concentrated in a rotary evaporator. Theresidue was purified by flash chromatography (SiO₂, 0-10% methanol indichloromethane) to yield a colorless solid.

[0449] MS (m/z): 482 (MH⁺)

[0450]¹H-NMR (CDCl₃) δ2.86-2-3.07 (series of m, 2 H), 3.61-3.71 (m, 1H), 3.78 (s, 3 H), 3.91-4.02 (m, 1 H), 5.99 (d, J=3.3 Hz, 2 H), 6.58 (s,1 H), 6.80-7.11 (series of m, 8 H), 7.31 (d, J=7.8 Hz, 1 H), 7.48 (d,J=7.6 Hz, 1 H), 7.82 (d, J=8.7 Hz, 2 H), 10.93 (s, 1 H)

EXAMPLE 661-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0451] A.1-(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethyloxycarbonyl)thiocarbamoyl]-2,3,4,9-tetrahydro-1H-β-carboline

[0452] A mixture of1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.66 g,9.08 mmol) (prepared according to the process as disclosed inWO97/43287, Intermediate 7, page 24) and Fmoc-isothiocyanate (2.82 g,10.14 mmol) was dissolved in dry dichloromethane (50 mL). The mixturewas stirred for 16 hours at ambient temperature, and then concentratedin vacuo. Purification by flash chromatography (0-10% methanol indichloromethane) yielded the protected thiourea as a pale yellow solid.

[0453] MS (m/z): 574 (MH⁺)

[0454]¹H-NMR (CDCl₃) δ2.86 (dd, J=12.9, 5.1 Hz, 1 H), 3.09 (dt, J=17.1,6.9 Hz, 1 H), 3.56 (dt, J=12.9, 5.1 Hz, 1 H), 4.19 (t, J=6.9 Hz, 1 H),4.43-4.53 (m, 2 H), 5.91 (s, 2 H), 6.70 (d, J=8 Hz, 1 H), 6.90 (br d,J=7.6 Hz, 1 H), 6.97 (br s, 1 H), 7.11-7.78 (series of m, 17 H)

[0455] B.1-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0456] A solution of the protected thiourea from Part A (4.78 g, 8.33mmol) in 20% (v/v) piperidine in methanol was heated to reflux for 5 h.The mixture was concentrated in vacuo to yield a crude residue which waspurified by flash chromatography (SiO₂, 0-10% methanol indichloromethane) to yield a yellow solid.

[0457] MS (m/z): 352 (MH⁺)

[0458]¹H-NMR (CDCl₃) δ2.69-2.87 (series of m, 2 H), 3.10-3.19 (m, 1 H),4.24 (br s, 1 H), 6.00 (d, J=3.3 Hz, 2 H), 6.72 (d, J=8.0 Hz, 1 H), 6.87(d, J=8.0 Hz, 1 H), 7.00-7.11 (series of m, 3 H), 7.30 (d, J=8.0 Hz,1H), 7.46 (d, J=7.7 Hz, 1H), 7.74 (brs, 3 H), 11.06 (s, 1 H)

[0459] C.1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0460] To a solution of the thiourea of Part B (227 mg, 0.65 mmol) wasadded β-bromoacetophenone (159 mg, 0.80 mmol) and triethylamine (0.40mL). This mixture was heated to 70° C. for 3 h, cooled to roomtemperature and concentrated in a rotary evaporator. The residue waspurified by flash chromatography (SiO₂, 0-10% methanol indichloromethane) to yield a pale yellow solid.

[0461] MS (m/z): 452 (MH⁺)

[0462]¹H-NMR (CDCl₃) δ2.87-2-3.06 (series of m, 2 H), 3.63-3.73 (m, 1H), 3.93-3.99 (m, 1 H), 5.99 (d, J=3.3 Hz, 2 H), 6.59 (s, 1 H),6.81-7.11 (series of m, 5 H), 7.25-7.69 (series of m, 6 H), 7.89 (d,J=7.4 Hz, 2 H), 10.95 (s, 1 H)

EXAMPLE 67 3-(2,3-Dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-3R-9H-pyrrolo[3,4-b]quinolinone

[0463] A: [2-(1H-Indol-3-yl)-ethyl]-(1-naphthalen-1-yl-ethyl)-amine wasprepared according to the process described in Kawate, T.; Yamanaka, M.;Nakagawa, M. in Heterocycles, 1999, 50, 1033

[0464] B: R- and S-Diastereomers of1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0465] [2-(1H-Indol-3-yl)-ethyl]-(1-naphthalen-1-yl-ethyl)-amine (1.0 g,3.18 mmol) and 2,3-dihydro-benzofuran-5-carbaldehyde (2.356 g, 15.92mmol) were stirred in p-xylene (20 mL) at 165° C. for 7 h. To thereaction mixture was added silica gel (10 g) and hexane (200 mL). Thereaction mixture was filtered and the colorless filtrate was discarded.The silica gel was washed with ethyl acetate (100 mL). The ethyl acetatesolvent was evaporated, the concentrated crude material was dissolved ina small amount of CH₂Cl₂ and packed on a silica gel column. The columnwas eluted with 5% ethyl acetate/hexane to yield two diastereomers.

[0466]1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1S-1H-β-carboline(the non-desired diastereomer A) (Rf=0.59 in 30% EtOAc/Hexane) wasobtained as yellow solid.

[0467]¹H NMR 300 MHz (CDCl₃) δ1.581.62 (d, 3H, J=6.5 Hz), 2.61 (m, 1H),2.91 (m, 1H), 3.05˜3.20 (m, 4H), 4.51 (t, 2H, J=8.8 Hz), 4.72 (m, 1H),4.81 (s, 1H), 6.68 (m, 1H), 6.92 (m, 4H), 7.05˜7.65 (m, 5H), 7.70˜7.95(m, 4H)

[0468] MS (m/z) MH⁺(445), MH⁻(443).

[0469]1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1R-1H-β-carboline(the desired diastereomer B) (Rf=0.51 in 30% EtOAc/Hexane) was obtainedas a yellow solid.

[0470]¹H NMR 300 MHz (CDCl₃) δ1.58 (d, 3H, J=6.5 Hz), 2.65 (m, 1H), 2.91(m, 2H), 3.05 (t, 2H, J=8.8 Hz), 3.15 (m, 1H), 4.51 (t, 2H, J=8.8 Hz),4.65 (m, 1H), 5.10 (s, 1H), 6.68 (m, 1H), 6.85 (s, 2H), 7.11 (m, 2H),7.20˜7.50 (m, 5H), 7.68 (m, 2H), 7.81 (m, 1H), 8.21 (m, 1H)

[0471] MS (m/z) MH⁺(445), MH⁻(443).

[0472] C: Conversion of S-diastereomer to R-diastereomer

[0473]1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1S-1H-β-carboline(the non-desired diastereomer A) (190 g, 0.428 mmol) was stirred in 1000mL CH₂Cl₂ with TFA (52 mL, 701 mol) at room temperature overnight. Thereaction was quenched with NaOH (35 g, 0.875 mol) in water (100 mL). Thereaction mixture was mixed well and then let stand for 0.5 hours, duringwhich time a precipitate formed. The precipitate was filtered, the solidwashed with water and dried under high vacuum to yield the product as asolid.

[0474] 1H NMR was identical to that of1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1R-1H-β-carboline(the desired diastereomer).

[0475] D:3-(2,3-Dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-1,2,3,4-tetrahydro-3R-9H-pyrrolo[3,4-b]quinolinone

[0476]1-(2,3-Dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1R-1H-β-carboline(0.6469 g, 1.46 mmol) and potassium-t-butoxide (0.279 g, 2.48 mmol) werestirred in DMF (14 mL) at room temperature. O₂ gas was bubbled into thereaction mixture overnight. The reaction was quenched with HCl (2.48 mL,1 N aqueous). Ethyl acetate (50 mL) and H₂O (50 mL) were then added. Theorganic layer was separated. The aqueous layer was extracted with ethylacetate (50 mL) and CH₂Cl₂ (50 mL). The organic layers were washed withbrine (3×50 mL) and dried over MgSO₄. The resulting product wasconcentrated and purified via silica gel (2% methanol/CH₂Cl₂) to yieldthe product as a yellow solid.

[0477]¹H NMR 300 MHz (CDCl₃) δ1.65 (d, 3H, J=6.5 Hz), 3.05 (t, 2H, J=8.8Hz), 4.01 (m, 2H), 4.51 (t, 2H, J=8.8 Hz), 4.68 (m, 1H), 5.31 (s, 1H),6.62 (s, 1H), 6.88˜7.89 (m, 12H), 8.25 (d, 1H)

[0478] MS (m/z) MH⁺(459), MH⁻(457).

[0479] E:3-(2,3-Dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-3R-9H-pyrrolo[3,4-b]quinolinone

[0480]3-(2,3-Dihydro-benzofuran-5-yl)-2-(1R-1-naphthalen-1-yl-ethyl)-1,2,3,4-tetrahydro-3R-9H-pyrrolo[3,4-b]quinolinone(24 mg, 0.0524 mmol) was dissolved in 5 mL ethanol. To the reactionmixture was added 10% Pd/C (50 mg) and HCl (1.0 M in diethyl ether (0.05mL, 0.05 mL)). The reaction mixture was stirred under 35 psi of H₂ gasfor 3 hours at room temperature. The catalyst was filtered away on aplug of Celite. The reaction mixture was concentrated to yield crudeproduct. Purification by preparative TLC (5% MeOH/CH₂Cl₂) yielded thetitle product as yellowish solid.

[0481]¹H NMR 300 MHz (CDCl₃) δ13.23 (d, 2H, J=8.8 Hz), 4.59 (t, 2H,J=8.8 Hz), 4.78 (m, 2H), 0.32 (s, 1H), 6.88(m, 1H), 7.31 (m, 2H), 7.72(m, 3H), 8.32 (m, 1H).

[0482] MS (m/z) MH⁺(305), MH⁻(303)

EXAMPLE 683-Benzo[1,3]dioxol-5-yl-2-(5-bromo-furan-2-carbonyl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one

[0483] To a solution of 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) in THF(20 mL) was added oxalyl chloride (0.66 mL, 7.541 mmol). 2 drops of DMFwere then added to the reaction mixture, with bubbles of CO observed tocome out vigorously. Oxalyl chloride ((COCl)₂) (0.1 mL) was then added.The reaction mixture was stirred at room temperature for 10 min and at90° C. for 10 min. Solvent and excess (COCl)₂ were taken off undervacuum to yield 5-bromo-furan-2-carbonyl chloride as a pale yellowcrystalline solid.

[0484] The solid 5-bromo-furan-2-carbonyl chloride was dissolved in THF(20 mL). A solution of3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolinone(2.1 g, 6.856 mmol) in THF (20 mL) was then added. Triethylamine (4.55mL, 32.64 mmol) and DMAP (40 mg, 0.327 mmol) were then added insequentially. A few drops of DMF were added to the reaction mixture tokeep the solution clear. The reaction mixture was stirred at roomtemperature for 4 hours and then concentrated under vacuum. The residuewas dissolved in CHCl₃ (200 mL) and washed with H₂O (3×200 mL). Theorganic layer was dried over MgSO₄ to yield the title product as anoff-white solid. No further purification was necessary.

[0485]¹H NMR 300 MHz (CD₃OD) δ4.87 (d, 1H, J=11.5 Hz), 5.19 (d, 1H,J=11.5 Hz), 5.78 (m, 2H), 6.24˜7.60 (m, 8H), 8.39 (d, 1H, J=8.3 Hz)

[0486] MS (m/z): 479, 481 (MH⁺), 479, 477 (MH⁻)

EXAMPLES 69 THROUGH 79

[0487] General Procedure

[0488]3-Benzo[1,3]dioxol-5-yl-2-(5-bromo-furan-2-carbonyl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(0.100 g, 0.2086 mmol) was stirred with a mixture of a suitablysubstituted boronic acid (0.2296 mmol, 1.1 eq), Pd(PPh₃)₄ (12.4 mg,0.01043 mmol), K₂CO₃ (86.4 mg, 0.6258 mmol) in 1,4-dioxane (8 mL) andH₂O(2 mL) was degased under N₂ and then stirred at 100° C. for 1.5hours. The crude reaction mixture was loaded onto a silica gelpreparative TLC plate and eluted with 5% CH₃OH/CH₂CL₂ to yield theisolated product as a solid.

[0489] Compound #110 (reacted with phenyl boronic acid)

[0490]¹H NMR 300 MHz (CD₃OD) δ5.19 (d, 1H, J=11.5 Hz), 5.42 (d, 1H,J=11.5 Hz), 5.93 (s, 2H), 6.38 (s, 1H), 6.74˜8.31 (m, 14H)

[0491] MS (m/z): 477 (MH⁺), 475 (MH⁻)

[0492] Compound #111 (reacted with 4-methylthiophenyl boronic acid)

[0493]¹H NMR 300 MHz (CD₃OD) δ5.21 (d, 1H, J=11.5 Hz), 5.44 (d, 1H,J=11.5 Hz), 5.91 (s, 2H), 6.40 (s, 1H), 6.77 (d, 1H, J=9.0 Hz), 6.98 (s,2H), 7.21˜7.81 (m, 11H), 8.31 (d, 1H, J=9.0 Hz)

[0494] MS (m/z): 523 (MH⁺), 521 (MH⁻)

[0495] Compound #112 (reacted with 3-thienyl boronic acid)

[0496]¹H NMR 300 MHz (CD₃OD) δ5.22 (d, 1H, J=11.5 Hz), 5.43 (d, 1H,J=11.5 Hz), 5.88 (s, 2H), 6.38 (s, 1H), 6.72˜8.38 (m, 12H)

[0497] MS (m/z): 483 (MH⁺), 481 (MH⁻)

[0498] Compound #116 (reacted with 4-methylphenyl boronic acid)

[0499]¹H NMR 300 MHz (CD₃OD) δ2.25 (s, 3H), 5.21 (d, 1H, J=11.5 Hz),5.42 (d, 1H, J=11.5 Hz), 5.80 (s, 2H), 6.38 (s, 1H), 6.74˜8.31 (m, 13H)

[0500] MS (m/z): 491 (MH⁺), 489(MH⁻)

[0501] Compound #113 (reacted with 2-nitrophenyl boronic acid)

[0502]¹H NMR 300 MHz (CD₃OD) δ5.25 (d, 1H, J=11.5 Hz), 5.42 (d, 1H,J=11.5 Hz), 5.88 (s, 2H), 6.39 (s, 1H), 6.68˜8.66 (m, 13H)

[0503] MS (m/z): 522 (MH⁺), 520 (MH⁻)

[0504] Compound #117 (reacted with 2-thienyl boronic acid)

[0505]¹H NMR 300 MHz (CD₃OD) δ5.19˜5.42 (m, 2H), 5.93 (s, 2H), 6.40 (s,1H), 6.74˜8.35 (m, 11H)

[0506] MS (m/z): 467 (MH⁺), 465 (MH⁻)

[0507] Compound #118 (reacted with 3,4-methylenedioxyphenyl boronicacid)

[0508]¹H NMR 300 MHz (CD₃OD) δ5.19˜5.42 (m, 2H), 5.93 (m, 4H), 6.38 (s,1H), 6.74˜8.31 (m, 12H)

[0509] MS (m/z): 521 (MH⁺), 519 (MH⁻)

[0510] Compound #119 (reacted with 4-cyanophenyl boronic acid)

[0511]¹H NMR 300 MHz (CD₃OD) δ5.21˜5.42 (m, 2H), 5.70 (m, 2H), 6.18 (s,1H), 6.60˜8.51 (m, 13H)

[0512] MS (m/z): 502 (MH⁺), 500 (MH⁻)

[0513] Compound #120 (reacted with 4-hydroxymethylphenyl boronic acid)

[0514]¹H NMR 300 MHz (CD₃OD) δ4.79 (s, 2H), 5.25 (d, 1H, J=11.5 Hz),5.52 (d, 1H, J=11.5 Hz), 5.89 (s, 2H), 6.48 (s, 1H), 6.70˜8.31 (m, 13H)

[0515] MS (m/z): 507 (MH⁺), 505 (MH⁻)

[0516] Compound #121 (reacted with 3-hydroxymethylphenyl boronic acid)

[0517]¹H NMR 300 MHz (CD₃OD) δ4.79 (s, 2H), 5.21 (d, 1H, J=11.5 Hz),5.48 (d, 1H, J=11.5 Hz), 5.89 (s, 2H), 6.31 (s, 1H), 6.62˜8.31 (m, 13H)

[0518] MS (m/z): 507 (MH⁺), 505 (MH⁻)

[0519] Compound #122 (reacted with 4-dimethylaminophenyl boronic acid)

[0520]¹H NMR 300 MHz (CD₃OD) δ5.21˜5.50 (d, 1H, J=11.5 Hz), 5.90 (s,2H), 6.40 (d, 1H), 6.64˜8.31 (m, 13H)

[0521] MS (m/z): 520 (MH⁺), 518 (MH⁻)

EXAMPLE 803-(2,3-Dihydro-benzofuran-5-yl)-2-pyrimidin-2-yl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#123)

[0522]3-(2,3-Dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one.HClsalt (0.15 g, 0.440 mmol) was stirred with chloropyrimidine (60.5 mg,0.528 mmol), KF (31 mg, 0.528 mmol) and DIEA (0.19 mL, 1.1 mmol) at 60°C. for 16 h. The reaction mixture was diluted with H₂O (20 mL). Thesolid was filtered and dried on a suction funnel under vacuum. Aftersilica gel preparative TLC, the title product was isolated as a yellowsolid.

[0523]¹H NMR 300 MHz (CDCl₃) δ3.10 (t, 2H, J=8.8 Hz), 4.52 (t, 2H, J=8.8Hz), 4.92 (m, 2H), 6.15˜8.45 (m, 10 H), 9.81 (br, s, 1H)

[0524] MS (m/z) 383(MH⁺), 381 (MH⁻).

EXAMPLE 813-Benzofuran-5-yl-2-(5-pyridin-2-yl-pyrimidin-2-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#126)

[0525] A: Benzofuran-5-carbaldehyde was prepared according to theprocess described by Hiroya, K.; Hashimura, K.; Ogasawara, K. inHeterocycles, 1994, Vol. 38, No. 11, 2463-72

[0526] B: 1-Benzofuran-5-yl-2,3,4,9-tetrahydro-1H-β-carboline wasprepared according to the process outlined in Example 12,

[0527]¹H NMR 300 MHz (CDCl₃) δ2.68˜2.95 (m, 2H), 3.10 (m, 1H), 3.28 (m,1H), 5.25 (s, 1H), 6.65 (s, 1H), 7.15 (m, 3H), 7.38 (m, 2H), 7.51 (m,1H), 7.58 (s, 1H), 8.22 (s, 1H)

[0528] MS (m/z) MH⁺(289), MH⁻(287).

[0529] C:1-Benzofuran-5-yl-2-(5-pyridin-2-yl-pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolinewas prepared according to the process outlined in Example 12.

[0530]¹H NMR 300 MHz (CDCl₃) δ3.00 (m, 2H), 3.40 (m, 1H), 5.11 (m, 1H),6.65 (s, 1H), 7.15˜8.00 (m, 12H), 8.61 (m, 1H), 8.91 (m, 1H), 8.22 (s,2H)

[0531] MS (m/z) MH⁺(444), MH⁻(442).

[0532] D:1-(5-benzofuryl)2,34,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carboline(30 mg, 0.06764 mmol) and KOtBu (12.9 mg, 0.115 mmol) were stirred inDMF (1 mL) under O₂ gas for 10 hours at room temperature. PreparativeTLC (5% methanol in CH₂Cl₂) yielded the title product as yellow solid.

[0533]¹H NMR 300 MHz (CD₃OD) δ5.15 (m, 2H), 6.55 (s, 1H), 6.82˜8.98 (m,15H)

[0534] MS (m/z) 458, (MH⁺), 456 (MH⁻).

EXAMPLE 823-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(1-oxy-pyridin-2-yl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#125)

[0535]3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-(3R)-9H-pyrrolo[3,4-b]quinolin-9-one(4.5 mg, 0.010 mmol) and mCPBA (1.73 mg, 0.010 mmol) were stirred in THF(2 mL). A few drops of DMF were added to make the solution clear. Thereaction mixture was stirred at room temperature for 80 hours and thenat 60° C. for 8 hours. Preparative TLC (10% MeOH in CH₂Cl₂) yielded thetitle product as off-white solid, with some recovered starting material

[0536]¹H NMR 300 MHz (CD₃OD) δ3.12 (t, 2H, J=8.8 Hz), 4.45 (t, 2H, J=8.8Hz), 6.35 (s, 1H), 6.55 (d, 1H), 7.21˜8.99 (m, 11H)

[0537] MS (m/z) 458, (MH⁺), 456 (MH⁻).

EXAMPLE 83 THROUGH 861-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline

[0538]2-(5-bromo-2-pyrimidinyl)-1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline(0.45 g, 1.00 mmol), 1,2-dimethyl-1H-imidazole (0.18 g, 1.87 mmol),Pd(OAc)₂ (12 mg, 0.05 mmol), PPh₃ (26 mg, 0.1 mmol) and K₂CO₃ (0.28 g, 2mmol) were stirred in 3.5 mL DMF at 140° C. for 14 hours. The mixturewas poured into aqueous 10% NaOH solution (50 mL). The resultingsolution was extracted with CH₂Cl₂ (3×50 mL) and dried over Na₂SO₄.Purification by preparative TLC yielded the title product as yellowpowder.

[0539]¹H NMR 300 MHz (CDCl₃) δ2.21 (s, 3H), 2.35 (s, 3H), 2.90 (m, 2H),3.10 (t, 2H, J=8.8. Hz), 3.35 (m, 1H), 4.52 (t, 2H, J=8.8. Hz), 4.91 (m,1H), 6.68˜7.61 (m, 10 H)

[0540] MS (m/z) 463 (MH⁺), 461 (MH⁻).

[0541] The following compounds were similarly prepared according to theprocedure described above with appropriate selection and substitution ofsuitably substituted reagents.

2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0542] MS (m/z) 539, (MH⁺), 537 (MH⁻).

3-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-β]quinolin-9-one(#128)

[0543]¹H NMR 300 MHz (CD₃OD) δ3.08 (t, 2H, J=9.5 Hz), 3.28 (s, 3H), 3.50(s, 3H), 4.42 (t, 2H, J=9.5 Hz), 5.02 (br, s, 2H), 6.24 (s, 1H), 6.63(m, 1H), 6.84 (s, 1H), 7.19 (m, 2H), 7.31 (m, 1H), 7.53 (s, 2H), 8.35(m, 3H)

[0544] MS (m/z) 477, (MH⁺), 475 (MH⁻).

2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#127)

[0545]¹H NMR 300 MHz (CD₃OD) δ1.90 (s, 3H), 2.21 (s, 2H), 3.12 (t, 2H,J=8.8 Hz), 4.48 (t, 2H, J=8.8 Hz), 5.12 (m, 2H), 6.15 (s, 1H), 6.61˜8.85(m, 15H)

[0546] MS (m/z) MH+(553), MH⁻(551).

EXAMPLE 873-(2,3-Dihydro-benzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#129)

[0547]3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-oneHCl (0.30 g, 0.88 mmol) and 2-bromo-pyridine (2 mL), Pd₂dba₃ (0.23 g,0.25 mmol), BINAP (0.47 g, 0.75 mmol) and NaOtBu (0.66 g, 6.87 mmol)were stirred in 1,4-dioxane (4 mL) at 90° C. for 1 hour. The resultingmixture was concentrated and then filtered on a plug of Celite withCH₂Cl₂. Purification by preparative TLC (5% CH₃OH/CH₂Cl₂) yielded thetitle product as a yellow solid.

[0548]¹H NMR 300 MHz (CD₃OD) δ2.92 (t, 2H, J=9.5 Hz), 4.40 (t, 2H, J=9.5Hz), 4.54 (d, 1H, J=22 Hz), 4.85 (d, 1H, J=22 Hz), 6.55 (m, 2H), 7.10(m, 3H), 7.35 (m, 4H), 8.02 (m, 1H), 8.30 (d, 1H, J=9.3 Hz)

[0549] MS (m/z) 382, (MH⁺), 380 (MH⁻)

EXAMPLE 883-Benzo[1,3]dioxol-5-yl-2-(4-imidazol-1-yl-phenyl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#133)

[0550] 3-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one (30.6 mg, 0.1 mmol),1-(4-bromo-phenyl)-1H-imidazole (22.3 mg, 0.1 mmol), Pd₂dba₃ (4.6 mg,0.005 mmol), biphenyl-2-yl-di-tert-butyl-phosphane 3.0 mg, 0.01 mmol)and NaOtBu (14 mg, 0.14 mmol) were stirred in 1,4-dioxane (0.6 mL) at89° C. for 17 hours. Purification by preparative TLC (5% CH₃OH/CH₂Cl₂)yielded the title product as yellow powder.

[0551]¹H NMR 300 MHz (CD₃OD) δ4.70 (d, 1H), 5.02 (d, 1H), 5.48 (s, 2H),5.88 (s, 2H), 6.75˜8.32 (m, 14H)

[0552] MS (m/z) MH⁺(449), MH⁻(447)

EXAMPLE 892-[2,3′]Bipyridinyl-6′-yl-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#134)

[0553] A:2-(5-Bromo-pyridin-2-yl)-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0554] 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline(11.6 g, 40 mmol), 2, 5-dibromopyridine (10.42 g, 44 mmol), Pd₂dba₃(1.465 g, 1.6 mmol), dppp (1.32 g, 3.2 mmol) and NaOtBu (5.38 g, 56mmol) were stirred in 60 mL DMF at 80° C. for 3 days. The reactionmixture was filtered through a plug of Celite with CH₂Cl₂. The reactionmixture was then concentrated, the crude mixture was then loaded on Foxycolumn (110 g silica gel) and eluted with ethyl acetate/hexane (3:7).The product crystallized out in test tubes. The product was concentratedand then recrystallized from THF to yield the product as yellowcrystals.

[0555]¹H NMR 400 MHz (THF-d8) δ0.91 (m, 1H), 1.15 (m, 1H), 1.25(t, 2H,J=9.5 Hz), 1.60 (m, 1H), 2.31 (m, 1H), 2.60 (t, 2H, J=9.5 Hz), 4.75 (d,1H, J=7.6 H), 5.02 (d, 1H, J=7.6 Hz), 5.10˜5.28 (m, 4H), 5.380 (m, 2H),5.58 (m, 1H), 5.72 (m, 1H), 6.28 (s, 1H), 8.12 (s, 1H)

[0556] MS (m/z) 446, 448 (MH⁺), 444, 446 (MH⁻).

[0557] B:2-[2,3′]Bipyridinyl-6′-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0558] The product from step A above (0.4 g, 0.896 mmol),2-tributylstannanyl-pyridine (0.8 g, 2.17 mmol) and Pd(PPh₃)₄ (0.12 g,0.104 mmol) were stirred in 1,4-dioxane (5 mL) at 88° C. for 24 h. Thereaction mixture was filtered through a plug of Celite with CH₂Cl₂ andthen concentrated to a small volume. Preparative TLC (3:7 ethylacetate/hexane; then 5% CH₃OH/CH₂Cl₂) yielded the product as a yellowsolid.

[0559]¹H NMR (CDCl₃) δ2.82 (m, 1H), 3.10 (m, 3H), 3.58 (m, 1H), 4.31 (m,1H), 4.53 (t, 2H, J=9.5 z), 6.71 (,d, 1H, J=7.6 Hz), 6.85 (d, 1H, J=7.6Hz)

[0560] MS (m/z) 445, (MH⁺), 443 (MH⁻)

[0561] C:2-[2,3′]Bipyridinyl-6′-yl-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#134)

[0562] Following the procedure describe in Example 19 with appropriateselection and substitution of reagents, yielded the title product as asolid.

[0563]¹H NMR 300 MHz (CDCl₃) δ3.16 (t, 2H, J=9.5 Hz), 4.43 (t, 2H, J=9.5Hz), 4.98˜5.20 (m, 2H), 6.12 (s, 1H), 6.60˜8.70 (15 H)

[0564] MS (m/z) 459 (MH⁺), 457 (MH⁻)

EXAMPLE 903-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(3-methyl-3H-imidazol-4-yl)-pyridin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#137)

[0565] A: 2-Chloro-5-(3-methyl-3H-imidazol4-yl)-pyridine

[0566] 2-Chloro-4-iodo-pyridine (0.239 g, 1 mmol), 1-methyl-1H-imidazole(0.41 g, 5 mmol), Pd(OAc)₂ (22.5 mg, 0.1 mmol), PPh₃ (53 mg, 0.2 mmol)and CS₂CO₃ (0.326 g, 1 mmol) were stirred in DMF (3 mL) at 120° C., for6 hours. Purification by preparative TLC yielded the product as an oilcontaining 1-methyl-1H-imidazole. The product was used for the next stepwithout further purification.

[0567]¹H NMR (CDCl3) δ3.68 (s, 3H), 7.19 (s, 1H), 7.27 (s, 1H), 7.56 (s,1H), 7.68 (dd, 1H), 8.45 (d, 1H)

[0568] MS (m/z) MH⁺(194).

[0569] B:3-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(3-methyl-3H-imidazol4-yl)-pyridin-2-yl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#137)

[0570]3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(0.127 g, 0.372 mmol), 2-chloro-5-(3-methyl-3 H-imidazol-4-yl)-pyridine(0.06 g, 0.31 mmol), Pd(OAc)₂ (3.5 mg, 0.0155 mmol),biphenyl-2-yl-dicyclohexyl-phosphane (5.43 mg, 0.0155 mmol) and NaOtBu(0.104 g, 1.085 mmol) were stirred in 1,4-dioxane (0.6 mL) at 90° C.Purification by preparative TLC (5% MeOH in CH₂Cl₂) yielded the productas yellow solid.

[0571]¹H NMR 300 MHz (CDCl₃) δ3.12 (t, 2H), 3.60 (s, 3H), 3.50 (t, 2H),5.12 (m, 2H), 6.08 (s, 1H), 6.70 (m, 2H), 7.20˜8.55 (m, 10 H)

[0572] MS (m/z) MH⁺(462), MH⁻(460)

EXAMPLE 912-[5-(3-Benzyl-3H-imidazol-4-yl)-pyridin-2-yl]-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#138)

[0573] A: 5-(3-Benzyl-3H-imidazol-4-yl)-2-chloro-pyridine

[0574] Following the procedure described in Example 90, Step A, withappropriate selection and substitution of reagents, yielded the productas a solid.

[0575]¹H NMR (CDCl₃) δ5.15 (s, 2H), 6.86˜8.30 (m, 10 H)

[0576] MS (m/z) MH⁺(270)

[0577] B: Following the procedure described in Example 90 Step B, withappropriate selection and substitution of reagents, yield the product asa solid.

[0578]¹H NMR 300 MHz (CD₃OD) δ3.12 (t, 2H), 3.60 (m, 2H), 4.55 (t, 2H),5.10 (m, 2H), 6.05 (s, 1H), 6.45˜8.54 (m, 12H)

[0579] MS (m/z) MH⁺(538), MH⁻(536).

EXAMPLE 923-(2,3-Dihydro-benzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(#136)

[0580]3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-(3R)-9H-pyrrolo[3,4-b]quinolin-9-oneHCl (0.0341 g, 0.1 mmol), 2-iodo-pyridine (0.0341 g, 0.2 mmol), Pd₂dba₃(22.9 mg, 0.025 mmol), BINAP (46.7 mg, 0.075 mmol) and NaOtBu (58 mg,0.6 mmol) were stirred in 1,4-dioxane (0.8 mL) at 50° C. for 3 hours.Purification by preparative TLC (5% methanol/CH₂Cl₂) yielded the productas a yellow solid.

[0581]¹H NMR 300 MHz (CD₃OD) δ2.92 (t, 2H, J=9.5 Hz), 4.40 (t, 2H, J=9.5Hz), 4.54 (d, 1H, J=22 Hz), 4.85 (d, 1H, J=22 Hz), 6.55 (m, 2H), 7.10(m, 3H), 7.35 (m, 4H), 8.02 (m, 1H), 8.30 (d, 1H, J=9.3 Hz)

[0582] MS (m/z) MH⁺(382), MH⁻(380)

[0583] HPLC trace: Chiral OD, methanol, 25° C., tr=5.201 min.

EXAMPLE 933-(2,3-dihydro-benzofurn-5-yl)-2-[5-(3H-imidazol-4-yl)-pyridin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one

[0584] A stirred solution of2-[5-(3-Benzyl-3H-imidazol-4-yl)-pyridin-2-yl]-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one(0.005 mmol, 1 equivalent), prepared as in Example 91, andp-toluenesulfonyl hydrazide (0.25 mmol, 50 equivalents) in CH₃OH (3 mL)at about 80° C. is added to a solution of sodium acetate (0.5 mmol, 100equiv.) in H₂O (2 mL) over about a 2 h period. The mixture is stirredfor about another 3 h at about 80° C., then cooled to about 25° C., andthe solvent evaporated. The residue is dissolved into CH₂Cl₂ (20 mL),washed with saturated aqueous NaCl (10 mL), dried (Na₂SO₄), andconcentrated to yield the title product.

EXAMPLE 943-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(2-methyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo3,4-b]quinolin-9-one

[0585] Following the procedure described in Example 93,2-[5-(3-benzyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one,prepared as in Example 86, is reacted to yield the title compound.

EXAMPLE 95 IN VITRO TESTING

[0586] Cyclic Nucleotide Phosphodiesterase (PDE) Assay

[0587] PDEV Isolation

[0588] PDEV was isolated from rabbit and human tissues according to theprotocol described by Boolell et al. (Boolell, M., Allen, M. J.,Ballard, S. A., Ge[o-Attee, S., Muirhead, G. J., Naylor, A. M.,Osterloh, I. H., and Gingell, C) in International Journal of ImpotenceResearch 1996 8, 47-52 with minor modifications.

[0589] Briefly, rabbit or human tissues were homogenized in an ice-coldbuffer solution containing 20 mM HEPES (pH 7.2), 0.25M sucrose, 1 mMEDTA, and 1 mM phenylmethylsulphonyl fluoride (PMSF). The homogenateswere centrifuged at 100,000 g for 60 minutes at 4° C. The supernatantwas filtered through 0.2 μM filter and loaded on a Pharmacia Mono Qanion exchange column (1 ml bed volume) that was equilibrated with 20 mMHEPES, 1 mM EDTA and 0.5 mM PMSF. After washing out unbound proteins,the enzymes were eluted with a linear gradient of 100-600 mM NaCl in thesame buffer (35 to 50 ml total, depending on the tissue. Enzymes fromthe skeletal muscle, corpus cavernosum, retina, heart and platelet wereeluted with 35, 40, 45, 50, and 50 ml respectively.) The column was runat a flow rate of 1 ml/min and 1 ml fractions were collected. Thefractions comprising various PDE activities were pooled separately andused in later studies.

[0590] Measurement of Inhibition of PDEV

[0591] The PDE assay was carried out as described by Thompson andAppleman in Biochemistry 1971 10, 311-316 with minor modifications, asnoted below.

[0592] The assays were adapted to a 96-well format. The enzyme wasassayed in 5 mM MgCl₂, 15 mM Tris HCl (pH 7.4), 0.5 mg/ml bovine serumalbumin, 1 μM cGMP or cAMP, 0.1 μCi [³H]-cGMP or [³H]-cAMP, and 2-10 μlof column elution. The total volume of the assay was 100 μl. Thereaction mixture was incubated at 30° C. for 30 minutes. The reactionwas stopped by boiling for 1 minute and then cooled down on ice. Theresulting [³H]5′-mononucleotides were further converted to uncharged[³H]-nucleosides by adding 25 μl 1 mg/ml snake venom (Ophiophagushannah) and incubating at 30° C. for 10 minute. The reaction was stoppedby the addition of 1 ml Bio-Rad AG1-X2 resin slurry (1:3). All thecharged nucleotides were bound by the resin and only uncharged[³H]-nucleosides remained in the supernatant after centrifuging. Analiquot of 200 μl was taken and counted by liquid scintillation. PDEactivity was expressed as pmol cyclic nucleotide hydrolyzed/min/ml ofenzyme preparation.

[0593] Inhibitor studies were carried out in assay buffer with a finalconcentration of 10% DMSO. Under these conditions, the hydrolysis ofproduct increased with time and enzyme concentration in a linearfashion.

EXAMPLE 96 In Vitro Determination of K_(i) for PhosphodiesteraseInhibitors

[0594] The assays were adapted to a 96-well format. Phosphodiesterasewas assayed in 5 mM MgCl₂, 15 mM Tris HCl (pH 7.4), 0.5 mg/ml bovineserum albumin, 30 nM ³H-cGMP and test compound at variousconcentrations. The amount of enzyme used for each reaction was suchthat less than 15% of the initial substrate was converted during theassay period. For all measurements, the test compound was dissolved anddiluted in 100% DMSO (2% DMSO in assay). The total volume of the assaywas 100 μl. The reaction mixture was incubated at 30° C. for 90 minutes.The reaction was stopped by boiling for 1 minute and then immediatelycooled by transfer to an ice bath. To each well was then added 25 μl 1mg/ml snake venom (Ophiophagus hannah) and the reaction mixtureincubating at 30° C. for 10 minute. The reaction was stopped by theaddition of 1 ml Bio-Rad AG1-X2 resin slurry (1:3). An aliquot of 200 μlwas taken and counted by liquid scintillation.

[0595] The % inhibition of the maximum substrate conversion (by theenzyme in the absence of inhibitor) was calculated for each testcompound concentration. Using GraphPad Prism's nonlinear regressionanalysis (sigmoidal dose response), the % inhibition vs log of the testcompound concentration was plotted to determine the IC₅₀. Underconditions where substrate concentration<<K_(m) of the enzyme(K_(m)=substrate concentration at which half of the maximal velocity ofthe enzyme is achieved), K_(i) is equivalent to the IC₅₀ value.

[0596] Following procedures as described herein, the compounds as listedin Tables 1-6 were prepared. PDEV inhibitory activities for thesecompounds are presented either as the IC₅₀ (μM), as a percent inhibitionat a given concentration of test compound or as a Ki value in the Tablesbelow. Unless otherwise noted, PDEV inhibitory activities were measuredusing human tissue. The abbreviation “stereo” refers to the stereogenicconfiguration, the abbreviation “Rac” shall denote a racemic mixture.TABLE 1

ID# R² Stereo IC₅₀ (nM)  4 3,4-methylenedioxyphenyl Rac 664 123,4-dimethoxyphenyl Rac 559 ^(a) 17 5-(2,3-dihydrobenzofuryl) Rac 65%Inh @ 10 μM 48 3,4-methylenedioxyphenyl R

[0597] TABLE 2

ID# R² Stereo IC₅₀ (nM) 3 3,4-methylenedioxyphenyl Rac 340 ^(a)

[0598] TABLE 3

ID# R² Stereo

R⁴ IC₅₀(nM) 1 3,4-methylene Rac 2-pyrimidinyl 5-(3,4-dimethoxy 0.165dioxyphenyl phenyl) 2 3,4-methylene Rac 2-pyrimidinyl 5-(4-methoxy 0.191dioxyphenyl phenyl) 7 3,4-methylene Rac 2-pyrimidinyl 5-(4-methyl 0.325dioxyphenyl phenyl) 11 3,4-methylene Rac 2-pyrimidinyl absent 3.73dioxyphenyl 35 3,4-methylene S 2-pyrimidinyl 5-(3,4-dimethoxy 1.42 ^(a)dioxyphenyl phenyl) 36 3,4-methylene R 2-pyrimidinyl 5-(3,4-dimethoxy0.075 dioxyphenyl phenyl) 55 3,4-methylene Rac 2-pyrimidinyi 5-bromo4.48 dioxyphenyl 56 3,4-methylene Rac 2-pyrimidinyl 5-(3-pyridinyl) 1.24dioxyphenyl 57 3,4-methylene Rac 2-pyrimidinyl 5-(4-pyridinyl) 0.84dioxyphenyl 15 3,4-dimethoxy Rac 2-pyrimidinyl 5-(3,4-dimethoxy 1156phenyl phenyl) 39 5-(2,3-dihydro- Rac 2-pyrimidinyl 5-(4-methoxy 0.47benzofuryl) phenyl) 66 5-(2,3-dihydro- R 2-pyrimidinyl 5-(4-methoxy 0.19benzofuryl) phenyl) 42 5-(2,3-dihydro- Rac 2-pyrimidinyl 5-(4-hydroxy1.06 benzofuryl) phenyl) 51 5-(2,3-dihydro- benzofuryl) Rac2-pyrimidinyl

1.70 52 5-(2,3-dihydro- benzofuryl) Rac 2-pyrimidinyl

0.40 ^(a) 61 5-(2,3-dihydro- Rac 2-pyrimidinyl 5-(2-pyridinyl) 1.03benzofuryl) 65 5-(2,3-dihydro- R 2-pyrimidinyl 5-(2-pyridinyl) 0.23benzofuryl) 70 5-(2,3-dihydro- Rac 2-pyrimidynyl 5-(3-pyridinyl) 2.10benzofuryl) 73 5-(2,3-dihydro- R 2-pyrimidynyl 5-(4-methoxy 0.170benzofuryl) phenyl) 74 5-(2,3-dihydro- Rac 2-pyrimidynyl 5-bromo 1.90benzofuryl) 76 5-(2,3-dihydro- R 2-pyrimidynyl 5-(2-pyridinyl) 0.230benzofuryl) 81 5-(2,3-dihydro- R 2-pyrimidynyl 5-(3,4-dimethoxy 0.230benzofuryl) phenyl) 84 5-(2,3-dihydro- S 2-pyrimidynyl 5-(4-methoxy 2.42benzofuryl) phenyl) 85 3,4-methylene dixoyphenyl Rac 2-pyrimidynyl

0.90 91 3,4-methylene Rac 2-thiazolyl 3-(4-methoxy 0.410 dixoyphenylphenyl) 96 3,4- Rac 2-pyrimidynyl 5-(4-methoxy 0.520 dihydrobenzo-phenyl) [1,4]-dioxin-6-yl 99 3,4-methylene Rac 2-pyrimidynyl5-(4-pyridinyl) 0.840 dixoyphenyl 100 3,4-methylene Rac 2-pyrimidynyl5-(3-pyridinyl) 0.520 dixoyphenyl 114 5-Indanyl Rac 2-pyrimidynyl5-(3,4,-methylene 1.14 dioxyphenyl) 123 5-(2,3-dihydro Rac 2-pyrimidynylabsent 12.8 benzofuryl) 124 3-thienyl Rac 2-pyrimidynyl 5-(3,4-dimethoxy4.132 phenyl) 125 5-(2,3-dihydro Rac 2-pyrimidynyl N-oxo-2-pyridinyl Ki= benzofuryl) 0.144 126 5-benzofuryl Rac 2-pyrimidynyl 5-(2-pyridinyl)Ki = 0.138 127 5-(2,3,-dihydro Rac 2-pyrimidynyl 5-(1-benzyl-2- Ki =benzofuryl) methyl-imidazolyl) 0.140 128 5-(2,3,-dihydro Rac2-pyrimidynyl 5-(1,2-dimethyl Ki = benzofuryl) imidazolyl) 0.300 1295-(2,3-dihydro Rac 2-pyridinyl absent Ki = benzofuryl) 0.650 1305-(2,3,-dihydro Rac 2-pyrimidynyl 5-bromo 1.9 benzofuryl) 1315-(2,3-dihydro Rac 2-pyridinyl 5-bromo Ki = benzofuryl) 1.55 1323,4-methylene Rac 2-pyridinyl absent dioxyphenyl 133 3,4-methylene Racphenyl 4-(1-imidazoiyl) Ki = dioxyphenyl 1.75 134 5-(2,3-dihydro Rac2-pyridinyl 5-(2-pyridinyl) Ki = benzofuryl) 1.10 136 5-(2,3-dihydro R2-pyridinyl absent Ki = benzofuryl) 0.18 137 5-(2,3-dihydro Rac2-pyridinyl 5-(5-(1-methyl)- benzofuryl) imidazolyl) 138 5-(2,3-dihydroRac 2-pyridinyl 5-(5-(1-benzyl)- benzofuryl) imidazolyl)

[0599] TABLE 4

ID# R² Stereo Y

R⁴ IC₅₀ (nM) 5 3,4- Rac CH₂ 4-pyridinyl absent 688 methylene dioxyphenyl6 3,4- Rac C(O)CH═ phenyl 4-methoxy 0.507 methylene CH carbonyldioxyphenyl 8 3,4- Rac C(O)— phenyl 4-carboxy 0.828 methylene CH═CHdioxyphenyl 9 3,4- Rac C(O) 2-benzo(b) 6-hydroxy 0.460 methylene furyldioxyphenyl 13 3,4- Rac C(O) 2-furyl 5-(3-tri 0.227 methylenefluoromethyl dioxyphenyl phenyl) 16 3,4- Rac C(O) 2-furyl 5-(4-nitro0.390 methylene phenyl) dioxyphenyl 18 3,4- Rac C(S) 1- absent 54%methylene imidazolyl Inh @ dioxyphenyl 10 μM 19 3,4- Rac CH₂ phenylabsent 234 methylene dioxyphenyl 21 3,4 Rac C(O) 2-furyl 5-(4- 1.93methylene methoxy dioxyphenyl phenyl) 22 3,4- Rac C(O) 2-furyl 5-(4-0.86 methylene hydroxy dioxyphenyl phenyl) 23 3,4- Rac C(O) 2-furyl5-(4-formyl 1.76 methylene phenyl) dioxyphenyl 24 3,4- Rac C(O) 2-furyl5-(4- 1.21 methylene methoxy dioxyphenyl carbonyl phenyl) 25 3,4- RacC(O) 3-pyridinyl 2-hydroxy 1.57 methylene dioxyphenyl 26 3,4- Rac C(O)2-furyl 5-(4-amino 1.92 methylene phenyl) dioxyphenyl 27 3,4- RacC(O)—O— phenyl absent 3.40 ^(a) methylene CH₂ dioxyphenyl 28 3,4- S CH₂phenyl absent 6881^(a) methylene dioxyphenyl 29 3,4- Rac C(O) 2-furyl5-(4- 1.05 methylene carboxy dioxyphenyl phenyl) 30 3,4- Rac C(O)2-furyl 5-bromo 5.20 ^(a) methylene dioxyphenyl 31 3,4- Rac C(O)— phenyl4-methoxy 11.20 methylene CH₂—CH₂ carbonyl dioxyphenyl 32 3,4- methylenedioxyphenyl Rac C(O) 2-benzo(b) furyl

3.40 33 3,4- Rac C(O)— phenyl 4-carboxy 3.40 methylene CH₂—CH₂dioxyphenyl 34 3,4- methylene dioxyphenyl Rac C(O)—CH₂—CH₂ phenyl

59.50 ^(a) 37 3,4- Rac C(O)O— 4-pyridinyl absent 5.72 methylene CH₂dioxyphenyl 44 3,4- methylene dioxyphenyl Rac C(O) 2-furyl

1.58 69 3,4- methylene dioxyphenyl R C(O) 2-furyl

0.32 45 3,4- methylene dioxyphenyl Rac C(O) 2-furyl

1.33 47 3,4- R CH₂ phenyl absent methylene dioxyphenyl 49 3,4- methylenedioxyphenyl Rac C(O) 2-benzo(b) furyl

1.127 ^(a) 50 3,4- R C(O) 2-furyl 5-(3-tri 0.61^(a) methylenefluoromethyl dioxyphenyl phenyl) 54 3,4- Rac CH₂ phenyl absent 234methylene dioxyphenyl 58 3,4- Rac C(O) 2-furyl 5-(4- 0.86 methylenehydroxy dioxyphenyl phenyl) 59 3,4- Rac C(O) 2-furyl 5-(3-tri 0.66methylene fluoromethyl dioxyphenyl phenyl) 20 5-(2,3- Rac C(O)— phenyl4-methoxy 0.530 dihydro- CH═CH carbonyl benzofuryl) 53 5-(2,3- RacC(O)O— 4-pyridinyl absent 5.340 ^(a) dihydro- CH₂ benzofuryl) 60 5-(2,3-Rac CH₂ phenyl absent dihydro- benzofuryl) 75 3,4- Rac C(O) phenylabsent 51.51 methylene dioxyphenyl 77 5-(2,3- R CH₂ phenyl absent 62.67dihydro- benzofuryl) 79 3,4- R C(O)O— 4-pyridinyl absent 34.78 methyleneCH₂ dioxyphenyl 80 3,4- S C(O)O— 4-pyridinyl absent 2.710 methylene CH₂dioxyphenyl 82 3,4- methylene dioxyphenyl R C(O) 2-furyl

0.320 86 5-(2,3- Rac C(O)O— phenyl 4-carboxy 3.310 dihydro- CH₂benzofuryl) 87 3,4- Rac C(O)O— phenyl 4-carboxy 1.560 methylene CH₂dioxyphenyl 88 3,4- Rac C(O) 2- 6-benzyloxy 1.430 methylene benzofuryldioxyphenyl 92 5-(2,3- Rac C(O)O— phenyl 4-methoxy 2.880 dihydro- CH₂carbonyl benzofuryl) 97 3,4- Rac C(O)O— phenyl absent 2.120 methyleneCH₂ dioxyphenyl 98 5-(2,3- Rac C(O) 2- absent 1.020 dihydro- benzofurylbenzofuryl) 101 3,4- Rac C(O)- phenyl absent 2.90 methylene cyclodioxyphenyl propyl 102 3,4- Rac C(O)CH₂ 3-pyridinyl absent 95.10methylene dioxyphenyl 103 3,4- Rac C(O)— phenyl absent 0.540 methyleneCH═CH dioxyphenyl 104 3,4- Rac C(O)—CH₂ 4-pyridinyl absent 87.050methylene dioxyphenyl 106 5-(2,3- diydro- benzofuryl Rac C(O) 2-furyl

1.30 107 3,4- Rac C(O)—NH— 4-pyridinyl absent 40.550 methylene CH₂dioxyphenyl 110 3,4- Rac C(O) 2-furyl 5-phenyl 0.755 methylenedioxyphenyl 111 3,4- Rac C(O) 2-furyl 5-(4-methyl 0.952 methylenethiophenyl) dioxyphenyl 112 3,4- Rac C(O) 2-furyl 5-(3-thienyl) 0.699methylene dioxyphenyl 113 3,4- Rac C(O) 2-furyl 5-(3- 0.812 methylenenitrophenyl) dioxyphenyl 115 5-(2,3- Rac C(O) 2- absent 14.3 dihydroimidazolyl benzofuryl) 116 3,4- Rac C(O) 2-furyl 5-(4methyl 4.01methylene phenyl) dioxyphenyl 117 3,4- Rac C(O) 2-furyl 5-(2-furyl) 4.75methylene dioxyphenyl 118 3,4- Rac C(O) 2-furyl 5-(3,4- 1.97 methylenemethylene dioxyphenyl dioxyphenyl 119 3,4- Rac C(O) 2-furyl 5-(4-cyano1.19 methylene phenyl) dioxyphenyl 120 3,4- Rac C(O) 2-furyl 5-(4- 1.22methylene hydroxy dioxyphenyl methyl phenyl) 121 3,4- Rac C(O) 2-furyl5-(3- 0.56 methylene hydroxy dioxyphenyl methyl phenyl) 122 3,4- RacC(O) 2-furyl 5-(4- 2.05 methylene dimethyl dioxyphenyl amino phenyl) 1355-(2,3- R C(O) S-2-oxa- 3-oxo-4,7,7- Ki = dihydro bicyclo trimethyl 13.9benzofuryl) [2.2.1] heptanyl 139 5-(2,3- R C(O) R-2-oxa- 3-oxo-4,7,7-dihydro bicyclo trimethyl benzofuryl) [2.2.1] heptanyl

[0600] TABLE 5

(As Racemate) ID # R² Y R³

R⁴ IC₅₀(nM) 63 3,4-methylene C(O)— methyl phenyl 4-methoxy 511 ^(a)dioxyphenyl CH═CH carbonyl

[0601] TABLE 6

(As Racemate) ID # R² Y R³

R⁴ IC₅₀ (nM) 64 3,4-methylene C(O)— methyl phenyl 4-methoxy 113 ^(a)dioxyphenyl CH═CH carbonyl

EXAMPLE 97 IN VIVO TESTING

[0602] Following the procedure disclosed by Carter et al., (Carter, A.J., Ballard, S. A., and Naylor, A. M.) in The Journal of Urology 1998,160, 242-246, the compounds as listed in Table 7 were tested for in vivoefficacy, with results as tabulated below. TABLE 7 ID # Efficacy 36Active 37 Active 65 Active 66 Active

EXAMPLE 98

[0603] As a specific embodiment of an oral composition, 100 mg of thecompound of Example 21 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

[0604] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

We claim:
 1. A compound of formula (I) or (II):

wherein R¹ is selected from the group consisting of hydrogen, carboxy,—C(O)—C₁-C₆alkyl, —C(O)—C₁-C₆alkoxy, —C(O)—NH—C₁-C₆alkyl-NH₂,—C(O)—NH—C₁-C₆alkyl-NHR^(A), —C(O)—NH—C₁-C₆alkyl-N(R^(A))₂, —C(O)—NH₂,—C(O)—NHR^(A), —C(O)—N(R^(A))₂, —C₁-C₆alkyl-NH₂, —C₁-C₆alkyl-NHR^(A),—C₁-C₆alkyl-N(R^(A))₂, —NH—C₁-C₆alkyl-N(R^(A))₂; where each R^(A) isindependently selected from the group consisting of C₁-C₆alkyl, aryl,C₁-C₆aralkyl and heteroaryl, where the aryl, aralkyl or heteroaryl maybe optionally substituted with one to three R^(B); where each R^(B) isindependently selected from the group consisting of halogen, nitro,cyano, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylcarbonyl, carboxyC₁-C₆alkyl,C₁-C₆alkylsulfonyl, trifluoromethyl, amino, di(C₁-C₆alkyl)amino,acetylamino, carboxyC₁-C₆alkylcarbonylamino, hydroxyC₁-C₆alkylamino,NHR^(A) and N(R^(A))₂; R² is selected from the group consisting ofC₅-C₁₀alkyl (optionally substituted with one to three substituentsindependently selected from halogen, hydroxy, nitro, amino, NHR^(A) orN(R^(A))₂), aryl (optionally substituted with one to three substituentsindependently selected from R^(C)), cycloalkyl (optionally substitutedwith one to three substituents independently selected from R^(A)),heteroaryl (optionally substituted with one to three substituentsindependently selected from R^(C)), and heterocycloalkyl (optionallysubstituted with one to three substituents independently selected fromR^(C)); where R^(C) is selected from the group consisting of halogen,nitro, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, NH₂, NH(C₁-C₆alkyl) and N(C₁-C₆alkyl)₂; R³ is selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆alkylcarbonyl,C₂-C₆alkenylcarbonyl and C₂-C₆alkynylcarbonyl; b is an integer from 0 to4; R⁴ is independently selected from the group consisting of halogen,hydroxy, carboxy, oxo, nitro, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆alkoxycarbonyl, trifluoromethyl, phenyl (wherein the phenyl groupmay be optionally substituted with one to three substituentsindependently selected from R^(D)), phenylsulfonyl, naphthyl,C₁-C₆aralkyl, —O-aralkyl, (wherein the aralkyl group may be optionallysubstituted with one to three substituents independently selected fromR^(D)), heteroaryl (wherein the heteroaryl may be optionally substitutedwith one to three substituents independently selected from R^(D)),heterocycloalkyl, NH₂, NHR^(A), N(R^(A))₂,

 where each R^(D) is independently selected from halogen, hydroxy,carboxy, oxo, C₁-C₄alkyl, C₁₋₄alkylthio, hydroxyC₁₋₄alkyl, C₁-C₄alkoxy,C₁-C₄alkyoxycarbonyl, C₁-C₄alkylcarbonyl, trifluoromethyl,trifluoromethoxy, NH₂, NHR^(A), N(R^(A))₂, C(O)N(R^(A))₂, SO₂N(R^(A))₂,acetylamino, nitro, cyano, formyl, C₁-C₆alkylsulfonyl, carboxyC₁-C₆alkyland aralkyl; c is an integer from 0 to 4; R⁵ is independently selectedfrom the group consisting of halogen, nitro, hydroxy, C₁-C₆alkyl,C₁-C₆alkoxy, —NH₂, —NHR^(A), —N(R^(A))₂, —OR^(A), —C(O)NH₂,—C(O)NHR^(A), —C(O)N(R^(A))₂, —NHC(O)R^(A), —SO₂NHR^(A), —SO₂N(R^(A))₂,where R^(A) is as defined above, phenyl (optionally substituted with oneto three substituents independently selected from R^(B)), heteroaryl(optionally substituted with one to three substituents independentlyselected from R^(B)) and heterocycloalkyl (optionally substituted withone to three substituents independently selected from R^(B)); a is aninteger from 0 to 1; Y selected from the group consisting of—C₁-C₆alkyl-, —C(O)—, —(C₁-C₆alkyl)carbonyl-, —(C₂-C₆alkenyl)carbonyl-,—(C₂-C₆alkynyl)carbonyl-, -carbonyl(C₁-C₆alkyl)-,-carbonyl(C₂-C₆alkenyl)-, —C(O)O—(C₁-C₆alkyl)-, —C(S)—, —SO₂—,—(C₁-C₆alkyl)sulfonyl-, -sulfonyl(C₁-C₆alkyl)-, —C(O)NH—,—C(O)NH—(C₁-C₆alkyl)-, C(O)(C₃-C₇cycloalkyl)- and—(C₃-C₇cycloalkyl)-C(O)—;

 is selected from the group consisting phenyl, furyl, thienyl andpyrrolyl;

 is selected from the group consisting of aryl, heteroaryl, cycloalkyland heterocycloalkyl; provided that when R¹ is hydrogen, R³ is hydrogen,b is 0, c is 0, a is 1, Y is —CH₂—,

 is phenyl and

 is phenyl, then R² is not trimethoxyphenyl; and pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1 wherein R¹ ishydrogen; R² is selected from the group consisting of phenyl (optionallysubstituted with one to two substituent selected from halogen, nitro,cyano, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, NH₂,NH(C₁-C₃alkyl) or N(C₁-C₃alkyl)₂), heteroaryl and heterocycloalkyl; R³is selected from the group consisting of H and C₁-C₄alkyl; b is aninteger from 0 to 4; R⁴ is selected from the group consisting ofhalogen, hydroxy, carboxy, oxo, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkoxycarbonyl, phenyl (wherein the phenyl may be optionallysubstituted with one to two substituents selected from hydroxy, carboxy,C₁-C₄alkyl, C₁₋₄alkylthio, hydroxyC₁₋₄alkyl, C₁-C₄alkoxy,C₁-C₄alkyoxycarbonyl, C(O)N(R^(A))₂, trifluoromethyl, trifluoromethoxy,amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, nitro, cyano or formyl),O-aralkyl, heteroaryl (wherein the heteroaryl may be optionallysubstituted with one to two substituents selected from hydroxy, carboxy,oxo, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyoxycarbonyl, C(O)N(R^(A))₂,trifluoromethyl, trifluoromethoxy, amino, nitro, C₁-C₃alkylcarbonyl orC₁₋₄aralkyl), heterocycloalkyl,

c is 0; a is an integer from 0 to 1; Y is selected from the groupconsisting of —C₁-C₄alkyl-, —C(S)—, —C(O)—, —C(O)O—(C₁-C₄alkyl)-,—C(O)—(C₁-C₄alkyl)-, —C(O)—(C₂-C₄alkenyl)-, C(O)—(C₃-C₇cycloalkyl)- and—C(O)NH—(C₁-C₃alkyl)-;

 is phenyl;

 is selected from the group consisting of phenyl, heteroaryl andheterocycloalkyl; and pharmaceutically acceptable salts thereof.
 3. Thecompound of claim 2 wherein R² is selected from the group consisting of3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,5-(2,3-dihydrobenzofuryl), 3,4-dihydrobenzo-[1,4]-dioxin-6-yl,5-benzofuryl, 5-indanyl and 3-thienyl; R³ is selected from the groupconsisting of H and methyl; R⁴ is selected from the group consisting ofbromo, hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl,3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl,4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl,4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-cyanophenyl,4-aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl,4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, N-oxy-2-pyridinyl, 3-thienyl, 2-furyl, 1-imidazolyl,5-(1-benzyl-2-methylimidazolyl), 5-(1,2-dimethylimidazolyl),5-(1-methylimidazoly), 5-(1-benzylimidazolyl), 3,4-methylenedioxyphenyl,

Y is selected from the group consisting of —CH₂—, —C(S)—, —C(O)—,—C(O)O—CH₂—, —C(O)—CH₂CH₂—, —C(O)—CH═CH—, —C(O)NH—CH₂— (107),—C(O)-cyclopropyl and —C(O)CH₂;

 is selected from the group consisting of phenyl, 2-furyl,2-benzo(b)furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-imidazolyl, 2-imidazolyl, 2-thiazolyl, and2-oxa-bicyclo[2.2.1]heptanyl; and pharmaceutically acceptable saltsthereof.
 4. The compound of claim 3 wherein R² is selected from thegroup consisting of 3,4-methylenedioxyphenyl, 5-(2,3-dihydrobenzofuryl),3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 3-thienyl, 5-indanyl and5-benzofuryl; R³ is H; b is in integer from 0 to 1; R⁴ is selected fromthe group consisting of 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy,phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl,4-carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl,3-trifluoromethylphenyl, 4-aminophenyl, 4-dimethylaminophenyl,3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furyl, 3-thienyl,N-oxo-2-pyridinyl, 1-imidazolyl, 5-(1-benzyl-2-methylimidazolyl),5-1,2-dimethylimidazolyl), 3,4-methylenedioxyphenyl,

Y is selected from the group consisting of —C(O)—, —C(O)O—CH₂—,—C(O)—CH₂CH₂—, —C(O)—CH═CH—, and —C(O)-cyclopropyl;

 is selected from the group consisting of phenyl, 2-furyl,2-benzo(b)furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyland 2-thiazolyl; and pharmaceutically acceptable salts thereof.
 5. Thecompound of claim 4 wherein R⁴ is selected from the group consisting of3,4-methylenedioxyphenyl, 5-(2,3-dihydrobenzofuryl),3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 3-thienyl, 5-indanyl and5-benzofuryl; R⁴ is selected from the group consisting of 5-bromo,2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl,3-hydroxymethylphenyl, 4-hydroxymethyphenyl, 4-carboxyphenyl,4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl,3-trifluoromethylphenyl, 4-aminophenyl, 4-dimethylaminophenyl,3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-thienyl,2-furyl, 1-imidazolyl, 5-(1-benzyl-2-methylimidazolyl),5-(1,2-dimethylimidazolyl), 3,4-methylenedioxyphenyl,

Y is selected from the group consisting of —C(O)—, —C(O)O—CH₂— and—C(O)—CH═CH—; and pharmaceutically acceptable salts thereof.
 6. Thecompound of claim 5 wherein R⁴ is selected from the group consisting of6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl,4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl,3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,N-oxo-2-pyridinyl, 3-thienyl, 5-(1-benzyl-2-methylimidazolyl),5-(1,2-dimethylimidazolyl),

and pharmaceutically acceptable salts thereof.
 7. The compound of claim6 wherein R² is selected from the group consisting of3,4-methylenedioxyphenyl, and 5-(2,3-dihydrobenzofuryl); R⁴ is selectedfrom the group consisting of hydroxy, 4-methylphenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl,4-nitrophenyl, 2-pyridinyl, 3-pyridinyl,

Y is selected from the group consisting of —C(O)— and —C(O)O—CH₂—;

 is selected from the group consisting of 2-furyl, 2-benzo(b)furyl,4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl; and pharmaceuticallyacceptable salts thereof.
 8. The compound of claim 7 selected from thegroup consisting of1,2,3,4-Tetrahydro-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;1,2,3,4-Tetrahydro-2-[(4-pyridinyl)methyloxycarbonyl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;2,3,4-Tetrahydro-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)-piperazinylcarbonyl)-phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one;1,2,3,4-tetrahydro-2-[2,3′-bipyridin]-6′-yl-3-(2,3-dihydro-5-benzofuranyl)-9H-pyrrolo[3,4-b]quinolin-9-one;2,3,4-tetrahydro-2-(2-pyridinyl)-3-(2,3-dihydro-5-benzofuranyl)-9H-pyrrolo[3,4-b]quinolin-9-one;and pharmaceutically acceptable salts thereof.
 9. The compound of claim8 selected from the group consisting ofR-1,2,3,4-Tetrahydro-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;R-1,2,3,4-Tetrahydro-2-[(4-pyridinyl)methyloxycarbonyl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;R-1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;R-1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo-[3,4-b]quinolin-9-one;R-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)-piperazinylcarbonyl)-phenyl)-furoyl)-9H-pyrrolo[3,4-b]quinolin-9-one;R-1,2,3,4-tetrahydro-2-(2-pyridinyl)-3-(2,3-dihydro-5-benzofuranyl)-9H-pyrrolo[3,4-b]quinolin-9-one;and pharmaceutically acceptable salts thereof.
 10. A compound of formula(I) or (II):

wherein R¹ is selected from the group consisting of hydrogen, carboxy,—C(O)—C₁-C₆alkyl, —C(O)—C₁-C₆alkoxy, —C(O)—NH—C₁-C₆alkyl-NH₂,—C(O)—NH—C₁-C₆alkyl-NHR^(A), —C(O)—NH₂, —C(O)—NHR^(A), —C(O)—N(R^(A))₂,—C₁-C₆alkyl-NH₂, —C₁-C₆alkyl-NHR^(A), —C₁-C₆alkyl-N(R^(A))₂,—NH—C₁-C₆alkyl-N(R^(A))₂; where each R^(A) is independently selectedfrom the group consisting of C₁-C₆alkyl, aryl, C₁-C₆aralkyl andheteroaryl, where the aryl, aralkyl or heteroaryl may be optionallysubstituted with one to three R^(B); where each R^(B) is independentlyselected from the group consisting of halogen, nitro, cyano, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkylcarbonyl, carboxyC₁-C₆alkyl, C₁-C₆alkylsulfonyl,trifluoromethyl, amino, di(C₁-C₆alkyl)amino, acetylamino,carboxyC₁-C₆alkylcarbonylamino, hydroxyC₁-C₆alkylamino, NHR^(A) andN(R^(A))₂; R² is selected from the group consisting of C₅-C₁₀alkyl(optionally substituted with one to three substituents independentlyselected from halogen, hydroxy, nitro, amino, NHR^(A) or N(R^(A))₂),aryl (optionally substituted with one to three substituentsindependently selected from R^(C)), cycloalkyl (optionally substitutedwith one to three substituents independently selected from R^(A)),heteroaryl (optionally substituted with one to three substituentsindependently selected from R^(C)), and heterocycloalkyl (optionallysubstituted with one to three substituents independently selected fromR^(C)); where R^(C) is selected from the group consisting of halogen,nitro, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, NH₂, NH(C₁-C₆alkyl) and N(C₁-C₆alkyl)₂; R³ is selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆alkylcarbonyl,C₂-C₆alkenylcarbonyl and C₂-C₆alkynylcarbonyl; b is an integer from 0 to4; R⁴ is independently selected from the group consisting of halogen,hydroxy, carboxy, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl,trifluoromethyl, phenyl (wherein the phenyl group may be optionallysubstituted with one to three substituents independently selected fromR^(D)), phenylsulfonyl, naphthyl, C₁-C₆aralkyl, —O-aralkyl, (wherein thearalkyl group may be optionally substituted with one to threesubstituents independently selected from R^(D)), heteroaryl (wherein theheteroaryl may be optionally substituted with one to three substituentsindependently selected from R^(D)), NH₂, NHR^(A), N(R^(A))₂,

where each R^(D) is independently selected from halogen, hydroxy,carboxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkyoxycarbonyl,C₁-C₄alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH₂, NHR^(A),N(R^(A))₂, C(O)N(R^(A))₂, SO₂N(R^(A))₂, acetylamino, nitro, cyano,formyl, C₁-C₆alkylsulfonyl and carboxyC₁-C₆alkyl; c is an integer from 0to 4; R⁵ is independently selected from the group consisting of halogen,nitro, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, —NH₂, —NHR^(A), —N(R^(A))₂,—OR^(A), —C(O)NH₂, —C(O)NHR^(A), —C(O)N(R^(A))₂, —NHC(O)R^(A),—SO₂NHR^(A), —SO₂N(R^(A))₂, where R^(A) is as defined above, phenyl(optionally substituted with one to three substituents independentlyselected from R^(B)), heteroaryl (optionally substituted with one tothree substituents independently selected from R^(B)) andheterocycloalkyl (optionally substituted with one to three substituentsindependently selected from R^(B)); a is an integer from 0 to 1; Yselected from the group consisting of —C₁-C₆alkyl-, —C(O)—,—(C₁-C₆alkyl)carbonyl-, —(C₂-C₆alkenyl)carbonyl-,—(C₂-C₆alkynyl)carbonyl-, -carbonyl(C₁-C₆alkyl)-,-carbonyl(C₂-C₆alkenyl)-, —C(O)O—(C₁-C₆alkyl)-, —C(S)—, —SO₂—,—(C₁-C₆alkyl)sulfonyl-, -sulfonyl(C₁-C₆alkyl)-, —C(O)NH—,—C(O)NH—(C₁-C₆alkyl)-, C(O)(C₃-C₇cycloalkyl)- and—(C₃-C₇cycloalkyl)-C(O)—;

 is selected from the group consisting phenyl, furyl, thienyl andpyrrolyl;

 is selected from the group consisting of aryl, heteroaryl, cycloalkyland heterocycloalkyl; provided that when R^(A) is hydrogen, R³ ishydrogen, b is 0, c is 0, a is 1, Y is —CH₂—,

 is phenyl and

 is phenyl, then R² is not trimethoxyphenyl; and pharmaceuticallyacceptable salts thereof.
 11. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of claim
 1. 12. Apharmaceutical composition made by mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 13. A process for making apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 14. A method of treating sexualdysfunction in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of the compound of claim 1.15. A method of treating sexual dysfunction in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the composition of claim
 11. 16. The method of treating sexualdysfunction of claim 14, wherein the sexual dysfunction is male sexualdysfunction, male erectile dysfunction, impotence, female sexualdysfunction, female sexual arousal dysfunction and female sexualdysfunction related to blood flow and nitric oxide production in thetissues of the vagina and clitoris.
 17. A method for increasing theconcentration of cGMP in penile tissue in a male subject in need thereofcomprising administering to the subject an effective amount of thecompound of claim
 1. 18. A method of treating a condition selected fromthe group consisting of male erectile dysfunction (ED), impotence,female sexual arousal dysfunction, female sexual dysfunction related toblood flow and nitric oxide production in the tissues of the vagina andclitoris, premature labor, dysmenorrhea, cardiovascular disorders,atherosclerosis, arterial occlusive disorders, thrombosis, coronary reststenosis, angina pectoris, myocardial infarction, heart failure,ischemic heart disorders, hypertension, pulmonary hypertension, asthma,intermittent claudication and diabetic complications in a subject inneed thereof comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1.